ORCID Profile
0000-0002-1366-6691
Current Organisation
La Trobe University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Cell Development, Proliferation and Death | Biochemistry and Cell Biology | Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Plant Developmental and Reproductive Biology | Analytical Chemistry | Haematology | Radiology and Organ Imaging | Signal Transduction | Flow Analysis
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences |
Related Links
Publications
A global metagenomic map of urban microbiomes and antimicrobial resistance
Publisher: Elsevier BV
Date: 06-2021
Association between targeted somatic mutation (TSM) signatures and HGS‐OvCa progression
Publisher: Wiley
Date: 03-08-2016
DOI: 10.1002/CAM4.825
Regulation of cellular and PCP signalling by the Scribble polarity module
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.SEMCDB.2017.11.021
Abstract: Since the first identification of the Scribble polarity module proteins as a new class of tumour suppressors that regulate both cell polarity and proliferation, an increasing amount of evidence has uncovered a broader role for Scribble, Dlg and Lgl in the control of fundamental cellular functions and their signalling pathways. Here, we review these findings as well as discuss more specifically the role of the Scribble module in PCP signalling.
Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis
Publisher: Proceedings of the National Academy of Sciences
Date: 30-05-2023
Abstract: G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D 3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.
Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module
Publisher: Springer Science and Business Media LLC
Date: 24-11-2008
DOI: 10.1038/ONC.2008.341
The polarity protein Scrib limits atherosclerosis development in mice
Publisher: Oxford University Press (OUP)
Date: 05-04-2019
DOI: 10.1093/CVR/CVZ093
Abstract: The protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions. Tamoxifen-induced Scrib-knockout mice were crossed with ApoE−/− knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine s les and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes. By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.
How to expel a bad tenant: Linking cyclin A2, enucleation and cell size
Publisher: Informa UK Limited
Date: 02-02-2017
Increasing Intracellular Bioavailable Copper Selectively Targets Prostate Cancer Cells
Publisher: American Chemical Society (ACS)
Date: 24-05-2013
DOI: 10.1021/CB400198P
Abstract: The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from Cu(II)(gtsm) but is retained by Cu(II)(atsm). We further demonstrated that intracellular H2gtsm [reduced Cu(II)(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both Cu(II)(gtsm) and Cu(II)(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both Cu(II)(gtsm) and Cu(II)(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with Cu(II)(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden (∼70%) and severity (grade), while treatment with Cu(II)(atsm) (30 mg/kg) was ineffective at the given dose. However, Cu(II)(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that Cu(II)(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.
Scrib:Rac1 interactions are required for the morphogenesis of the ventricular myocardium
Publisher: Oxford University Press (OUP)
Date: 18-08-2014
DOI: 10.1093/CVR/CVU193
Cell-intrinsic requirement for pRb in erythropoiesis
Publisher: American Society of Hematology
Date: 09-2004
DOI: 10.1182/BLOOD-2004-02-0618
Abstract: Retinoblastoma (Rb) and family members have been implicated as key regulators of cell proliferation and differentiation. In particular, accumulated data have suggested that the Rb gene product pRb is an important controller of erythroid differentiation. However, current published data are conflicting as to whether the role of pRb in erythroid cells is cell intrinsic or non–cell intrinsic. Here, we have made use of an in vitro erythroid differentiation culture system to determine the cell-intrinsic requirement for pRb in erythroid differentiation. We demonstrate that the loss of pRb function in primary differentiating erythroid cells results in impaired cell cycle exit and terminal differentiation. Furthermore, we have used coculture experiments to establish that this requirement is cell intrinsic. Together, these data unequivocally demonstrate that pRb is required in a cell-intrinsic manner for erythroid differentiation and provide clarification as to its role in erythropoiesis.
Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-10-2020
Abstract: Bcl-2 proteins are molecular gatekeepers of the mitochondrial pathway of apoptosis that emerged early during metazoan evolution.
Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain
Publisher: Springer Science and Business Media LLC
Date: 11-06-2021
DOI: 10.1038/S42003-021-02250-7
Abstract: SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex. We show that C-terminal PDZ binding motifs of SARS-CoV-1 and SARS-CoV-2 E proteins bind the PALS1 PDZ domain with 29.6 and 22.8 μM affinity, whereas the related sequence from MERS-CoV did not bind. We then determined crystal structures of PALS1 PDZ domain bound to both SARS-CoV-1 and SARS-CoV-2 E protein PDZ binding motifs. Our findings establish the structural basis for SARS-CoV-1/2 mediated subversion of Crumbs polarity signalling and serve as a platform for the development of small molecule inhibitors to suppress SARS-CoV-1/2 mediated disruption of polarity signalling in epithelial cells.
The Scribble–Dlg–Lgl Module in Cell Polarity Regulation
Publisher: Springer International Publishing
Date: 2015
E2F4 Is Essential for Normal Erythrocyte Maturation and Neonatal Viability
Publisher: Elsevier BV
Date: 08-2000
DOI: 10.1016/S1097-2765(00)00029-0
Abstract: The retinoblastoma protein (pRB) plays a key role in the control of normal development and proliferation through the regulation of the E2F transcription factors. We generated a mutant mouse model to assess the in vivo role of the predominant E2F family member, E2F4. Remarkably, loss of E2F4 had no detectable effect on either cell cycle arrest or proliferation. However, E2F4 was essential for normal development. E2f4-/- mice died of an increased susceptibility to opportunistic infections that appeared to result from craniofacial defects. They also displayed a variety of erythroid abnormalities that arose from a cell autonomous defect in late stage maturation. This suggests that E2F4 makes a major contribution to the control of erythrocyte development by the pRB tumor suppressor.
Lethal giant larvae‐1 deficiency enhances the CD8+ effector T‐cell response to antigen challenge in vivo
Publisher: Wiley
Date: 22-09-2015
DOI: 10.1038/ICB.2015.82
Abstract: Lethal giant larvae-1 (Lgl-1) is an evolutionary conserved protein that regulates cell polarity in erse lineages however, the role of Lgl-1 in the polarity and function of immune cells remains to be elucidated. To assess the role of Lgl-1 in T cells, we generated chimeric mice with a hematopoietic system deficient for Lgl-1. Lgl-1 deficiency did not impair the activation or function of peripheral CD8(+) T cells in response to antigen presentation in vitro, but did skew effector and memory T-cell differentiation. When challenged with antigen-expressing virus or tumor, Lgl-1-deficient mice displayed altered T-cell responses. This manifested in a stronger antiviral and antitumor effector CD8(+) T-cell response, the latter resulting in enhanced control of MC38-OVA tumors. These results reveal a novel role for Lgl-1 in the regulation of virus-specific T-cell responses and antitumor immunity.
The Scribble and Par complexes in polarity and migration: friends or foes?
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.TCB.2006.10.005
Abstract: The Par complex [consisting of Bazooka (also called Par3), Par6 and aPKC] is a well-described regulator of cell polarity whose role in many aspects of cell morphogenesis is under intense investigation. Recently, another set of proteins known as the Scribble complex (consisting of Scribble, Discs large and Lethal giant larvae) has also been shown to be important in polarity regulation in several settings. Here, we describe the current status of Scribble in polarity and review evidence from various model systems that indicates an essential but context-dependent role for the Scribble and Par complexes in directed cell migration. Based on the known interactions of Scribble and Par complexes with each other and with other signalling pathways, we propose models by which Par and Scribble might interact to regulate cell migration.
Crystal structure of the human Scribble PDZ1 domain bound to the PDZ-binding motif of APC.
Publisher: Wiley
Date: 02-02-2019
Abstract: Scribble (SCRIB) is an important adaptor protein that controls the establishment and maintenance of apico-basal cell polarity. To better understand how SCRIB controls cell polarity signalling via its PDZ domains, we investigated human SCRIB interactions with adenomatous polyposis coli (APC). We show that SCRIB PDZ1, PDZ2 and PDZ3 are the major interactors with the APC PDZ-binding motif (PBM), whereas SCRIB PDZ4 does not show detectable binding to APC. We then determined the crystal structure of SCRIB PDZ1 domain bound to the APC PBM. Our findings reveal a previously unreported pattern of interactions between the SCRIB PDZ domain region with the C-terminal PDZ binding motif of APC, where SCRIB PDZ1 domain is the highest affinity site.
Asymmetric Cell Division of T Cells upon Antigen Presentation Uses Multiple Conserved Mechanisms
Publisher: The American Association of Immunologists
Date: 07-2010
Abstract: Asymmetric cell ision is a potential means by which cell fate choices during an immune response are orchestrated. Defining the molecular mechanisms that underlie asymmetric ision of T cells is paramount for determining the role of this process in the generation of effector and memory T cell subsets. In other cell types, asymmetric cell ision is regulated by conserved polarity protein complexes that control the localization of cell fate determinants and spindle orientation during ision. We have developed a tractable, in vitro model of naive CD8+ T cells undergoing initial ision while attached to dendritic cells during Ag presentation to investigate whether similar mechanisms might regulate asymmetric ision of T cells. Using this system, we show that direct interactions with APCs provide the cue for polarization of T cells. Interestingly, the immunological synapse disseminates before ision even though the T cells retain contact with the APC. The cue from the APC is translated into polarization of cell fate determinants via the polarity network of the Par3 and Scribble complexes, and orientation of the mitotic spindle during ision is orchestrated by the partner of inscuteable/G protein complex. These findings suggest that T cells have selectively adapted a number of evolutionarily conserved mechanisms to generate ersity through asymmetric cell ision.
The Polarity Protein Scribble Regulates Myelination and Remyelination in the Central Nervous System
Publisher: Public Library of Science (PLoS)
Date: 25-03-2015
Asymmetric cell division during T cell development controls downstream fate
Publisher: Rockefeller University Press
Date: 14-09-2015
Abstract: During mammalian T cell development, the requirement for expansion of many in idual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell ision (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent isions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.
Transcriptional output of the Salvador/warts/hippo pathway is controlled in distinct fashions in Drosophila melanogaster and mammalian cell lines.
Publisher: American Association for Cancer Research (AACR)
Date: 29-07-2009
DOI: 10.1158/0008-5472.CAN-08-4592
Abstract: The Salvador/Warts/Hippo (SWH) pathway is an important modulator of organ size, and deregulation of pathway activity can lead to cancer. Several SWH pathway components are mutated or expressed at altered levels in different human tumors including NF2, LATS1, LATS2, SAV1, and YAP. The SWH pathway regulates tissue growth by restricting the activity of the transcriptional coactivator protein known as Yorkie (Yki) in Drosophila melanogaster and Yes-associated protein (YAP) in mammals. Yki/YAP drives tissue growth in partnership with the Scalloped (Sd)/TEAD1-4 transcription factors. Yki/YAP also possesses two WW domains, which contact several proteins that have been suggested to either promote or inhibit the ability of Yki to induce transcription. To investigate the regulatory role of the Yki/YAP WW domains, we analyzed the functional consequence of mutating these domains. WW domain mutant YAP promoted transformation and migration of breast epithelial cells with increased potency, suggesting that WW domains mediate the inhibitory regulation of YAP in these cells. By contrast, the WW domains were required for YAP to promote NIH-3T3 cell transformation and for the ability of Yki to drive tissue growth in D. melanogaster and optimally activate Sd. This shows that Yki/YAP WW domains have distinct regulatory roles in different cell types and implies the existence of proteins that promote tissue growth in collaboration with Yki and Sd. [Cancer Res 2009 (15):6033–41]
Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer
Publisher: Wiley
Date: 19-05-2003
DOI: 10.1002/BIES.10286
Abstract: Dlg (Discs large), Scrib (Scribble) and Lgl (Lethal giant larvae) are evolutionarily conserved components of a common genetic pathway that link the seemingly disparate functions of cell polarity and cell proliferation in epithelial cells. dlg, scrib and lgl have been identified as tumour suppressor genes in Drosophila, mutations of which cause similar phenotypes, involving disruption of cell polarity and neoplastic overgrowth of tissues. The molecular mechanisms by which Dlg, Scrib and Lgl proteins regulate cell proliferation are not clear, but there is some evidence that epithelial polarisation is required for this regulation. Dlg, Scrib and Lgl are highly conserved between human and Drosophila, and we discuss evidence that these proteins also play a role in cancer progression in humans.
The Scribble-Dlg-Lgl polarity module in development and cancer: From flies to man
Publisher: Portland Press Ltd.
Date: 28-08-2012
DOI: 10.1042/BSE0530141
Abstract: The Scribble, Par and Crumbs modules were originally identified in the vinegar (fruit) fly, Drosophila melanogaster, as being critical regulators of apico–basal cell polarity. In the present chapter we focus on the Scribble polarity module, composed of Scribble, discs large and lethal giant larvae. Since the discovery of the role of the Scribble polarity module in apico–basal cell polarity, these proteins have also been recognized as having important roles in other forms of polarity, as well as regulation of the actin cytoskeleton, cell signalling and vesicular trafficking. In addition to these physiological roles, an important role for polarity proteins in cancer progression has also been uncovered, with loss of polarity and tissue architecture being strongly correlated with metastatic disease.
A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer
Publisher: Public Library of Science (PLoS)
Date: 16-10-2018
Figure S7 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532960.V1
Abstract: Supplementary Figure 7: Characterization of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tumors. Representative images of IHC to detect (A) PCNA and (B) Cleaved-caspase 3 (CC3) in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl =100 d old. Quantitative RT-PCR to detect (C) Nkx3.1 and (D) Pbsn mRNA in Wt prostate and Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched prostate carcinomas (n = 5). Error bars: SEM, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Western Blotting of protein lysates isolated from Wt prostate and stage-matched Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate carcinomas to detect total AKT, p-AKT Thr308 and p-AKT Ser473 (n = 3).
Erratum: The tumour-suppressor scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge
Publisher: Springer Science and Business Media LLC
Date: 16-08-2007
An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery.
Publisher: The Company of Biologists
Date: 2012
DOI: 10.1242/DMM.009985
Abstract: Anti-cancer drug development involves enormous expenditure and risk. Key to the rapid and economic identification of novel, bioavailable anti-tumor chemicals is the use of appropriate in vivo tumor models suitable for large-scale screening. Using a Drosophila Ras-driven tumor model, we demonstrate that tumor overgrowth can be curtailed by feeding larvae chemicals with the in vivo pharmacokinetics essential for drug development and known efficacy against human tumor cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumor model. In a proof-of-principle pilot screen of 2000 compounds we identify the glutamine analog, Acivicin, a chemical with known activity against human tumor cells, as a potent and specific inhibitor of Drosophila tumor formation. RNAi-mediated knockdown of candidate Acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible critical target of Acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumors are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economic tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering wide spread applications in drug development.
Author Reply to Peer Reviews of Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition
Publisher: EMBO
Date: 16-07-2022
The Asymmetric Cell Division Regulators Par3, Scribble and Pins/Gpsm2 Are Not Essential for Erythroid Development or Enucleation
Publisher: Public Library of Science (PLoS)
Date: 17-01-2017
Stepwise progression of β-selection during T cell development as revealed by histone deacetylation inhibition
Publisher: Cold Spring Harbor Laboratory
Date: 04-10-2021
DOI: 10.1101/2021.10.03.462949
Abstract: During T cell development, the first step in creating a unique T Cell Receptor (TCR) is the genetic recombination of the TCRβ chain. The quality of the newly recombined TCRβ is assessed at the β-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of the complex events that control fate at the β-selection checkpoint is not yet understood. We shed new light on fate determination during β-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the β-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in β-selection, bookended by upregulation of the TCR co-receptors, CD28 and CD2 respectively. Within this ‘DN3b Pre’ stage, CD5 and Lef1 are upregulated to reflect pre-TCR signalling and their expression correlates with proliferation. During this phase, ACY1215-mediated disruption of the organisation of the β-selection immunological synapse is associated with a breakdown in connectivity of expression of pre-TCR, CD5 and Lef1. Subsequent deregulation of pre-TCR-induced proliferation leads to bypass of the β-selection checkpoint and subsequent failure to progress. We propose that the progressive expression of CD28, CD5 and Lef1, then CD2 reports and modulates the pre-TCR signal to orchestrate passage through the β-selection checkpoint. These findings suggest a refined model of β-selection in which a coordinated increase in expression of pre-TCR, CD28, CD5 and Lef1 allows for modulating TCR signalling strength, and culminates in the expression of CD2 to enable exit from the β-selection checkpoint.
Sorption of hydrophobic organic contaminants on functionalized biochar: Protagonist role of π-π electron-donor-acceptor interactions and hydrogen bonds
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JHAZMAT.2018.08.005
Abstract: The sorption of five potent endocrine disruptors as representative hydrophobic organic contaminants (HOCs) namely estrone (E1), 17β-estradiol (E2), estriol (E3), 17α-ethynylestradiol (EE2) and bisphenol A (BPA) on functionalized biochar (fBC) was systematically examined, with a particular focus on the importance of π-electron-donor (phenanthrene: PHEN) and π-electron-acceptors (1,3-dinitrobenzene: DNB, p-amino benzoic acid: PABA) on sorption. Experimental results suggested that hydrogen-bond formation and π-π-electron-donor-acceptor (EDA) interactions were the dominant sorption mechanisms. The sorption of HOCs decreased as E1 > E2 > EE2 > E3 > BPA based on the Freundlich and Polanyi-Mane-models. The comparison of adsorption coefficient (K
Localization, Not Important in All Tumor-Suppressing Properties: A Lesson Learnt from Scribble
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000348423
Abstract: Aberrant localization of proteins is increasingly being suggested as a causal player in epithelial cancers. Despite this, few studies have investigated how mislocalization of a protein can alter in idual biological processes that contribute to cancer progression. Using Ras as a model of transformation, we investigate how localization of the polarity protein Scribble contributes to its tumor-suppressive properties. Wild-type Scribble has been shown to modulate Ras-mitogen-activated protein kinase (MAPK) transformation both in vitro and in vivo. By utilizing a construct that carries a mutation in the LRR domain of Scribble (Scribble P305L) resulting in a cytosolic rather than the usual membrane-bound localization, we report that discrete tumor suppressive properties of Scribble are differentially sensitive to the localization of Scribble. We find that although the Scribble P305L mislocalization mutant can no longer suppress Ras-MAPK-induced invasion or epithelial to mesenchymal transition phenotypes, mislocalized Scribble can still suppress anchorage-independent cell growth. This study illustrates that the manner in which protein mislocalization contributes to cancer is likely complex and highlights the need for careful interrogation as to how cell polarity protein mislocalization, its secondary consequences, and the mutations that give rise to their mislocalization may contribute to specific aspects of cancer progression.
Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway
Publisher: Elsevier BV
Date: 07-2010
Tumor Suppressor Scribble Regulates Assembly of Tight Junctions in the Intestinal Epithelium
Publisher: Elsevier BV
Date: 2010
VANGL2 regulates luminal epithelial organization and cell turnover in the mammary gland
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
DOI: 10.1038/S41598-019-43444-8
Abstract: The VANGL family of planar cell polarity proteins is implicated in breast cancer however its function in mammary gland biology is unknown. Here, we utilized a panel of Vang1 and Vangl2 mouse alleles to examine the requirement of VANGL family members in the murine mammary gland. We show that Vang1CKO Δ/Δ glands display normal branching while Vangl2 flox/flox and Vangl2 Lp/Lp tissue exhibit several phenotypes. In MMTV - Cre Vangl2 flox/flox glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2 Lp/Lp tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2 Lp/Lp outgrowths, three morphological phenotypes are observed: distended ducts, supernumerary end buds, and ectopic acini. Layer specific defects are observed with loss of Vangl2 selectively in either basal or luminal layers of mammary cysts. Loss in the basal compartment inhibits cyst formation, but has the opposite effect in the luminal compartment. Candidate gene analysis on MMTV - Cre Vangl2 flox/flox and Vangl2 Lp/Lp tissue reveals a significant reduction in Bmi1 expression, with overexpression of Bmi1 rescuing defects in Vangl2 knockdown cysts. Our results demonstrate that VANGL2 is necessary for normal mammary gland development and indicate differential functional requirements in basal versus luminal mammary compartments.
The Scribble Cell Polarity Module in the Regulation of Cell Signaling in Tissue Development and Tumorigenesis
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.JMB.2018.01.011
Abstract: The Scribble cell polarity module, comprising Scribbled (Scrib), Discs-large (Dlg) and Lethal-2-giant larvae (Lgl), has a tumor suppressive role in mammalian epithelial cancers. The Scribble module proteins play key functions in the establishment and maintenance of different modes of cell polarity, as well as in the control of tissue growth, differentiation and directed cell migration, and therefore are major regulators of tissue development and homeostasis. Whilst molecular details are known regarding the roles of Scribble module proteins in cell polarity regulation, their precise mode of action in the regulation of other key cellular processes remains enigmatic. An accumulating body of evidence indicates that Scribble module proteins play scaffolding roles in the control of various signaling pathways, which are linked to the control of tissue growth, differentiation and cell migration. Multiple Scrib, Dlg and Lgl interacting proteins have been discovered, which are involved in erse processes, however many function in the regulation of cellular signaling. Herein, we review the components of the Scrib, Dlg and Lgl protein interactomes, and focus on the mechanism by which they regulate cellular signaling pathways in metazoans, and how their disruption leads to cancer.
Supplemetary Material and Tables from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progre
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532957.V1
Abstract: Supplemetary Material and Tables S1 - S7
Muscle Stem Cell Fate Is Controlled by the Cell-Polarity Protein Scrib
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.CELREP.2015.01.045
Abstract: Satellite cells are resident skeletal muscle stem cells that supply myonuclei for homeostasis, hypertrophy, and repair in adult muscle. Scrib is one of the major cell-polarity proteins, acting as a potent tumor suppressor in epithelial cells. Here, we show that Scrib also controls satellite-cell-fate decisions in adult mice. Scrib is undetectable in quiescent cells but becomes expressed during activation. Scrib is asymmetrically distributed in iding daughter cells, with robust accumulation in cells committed to myogenic differentiation. Low Scrib expression is associated with the proliferative state and preventing self-renewal, whereas high Scrib levels reduce satellite cell proliferation. Satellite-cell-specific knockout of Scrib in mice causes a drastic and insurmountable defect in muscle regeneration. Thus, Scrib is a regulator of tissue stem cells, controlling population expansion and self-renewal with Scrib expression dynamics directing satellite cell fate.
Figure S6 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532963.V1
Abstract: Supplementary Figure 6: Pik3ca+/HR and Ptenfl/fl prostate cancers acquire CRPC, while Pik3ca+/HR Ptenfl/fl mutants are resistant to castration. (A) Representative H& E images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl anterior (AP) and ventral (VP) prostate lobes post-castration (scale bar: 50 um, n = 3). (B) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue stained to detect Androgen receptor (AR) 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl = 100 d old. Insert displays positive AR nuclei (arrows) in Pik3ca+/HR Ptenfl/fl compound mutants (scale bar: 5 um). (C) Bar chart displaying total prostate weight normalised to body weight for Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (n = 8, 7 and 7, respectively). Error bars: SEM, *P .05 compared to 0 weeks post-castration, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (D) Representative H& E images of Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (scale bar: 100 um). Mice were castrated at 100 d of age.
Physiological Levels of Pik3caH1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors
Publisher: Public Library of Science (PLoS)
Date: 30-05-2012
Stepwise progression of β-selection during T cell development involves histone deacetylation
Publisher: Life Science Alliance, LLC
Date: 25-10-2022
Abstract: During T cell development, the first step in creating a unique T cell receptor (TCR) is genetic recombination of the TCRβ chain. The quality of the new TCRβ is assessed at the β-selection checkpoint. Most cells fail this checkpoint and die, but the coordination of fate at the β-selection checkpoint is not yet understood. We shed new light on fate determination during β-selection using a selective inhibitor of histone deacetylase 6, ACY1215. ACY1215 disrupted the β-selection checkpoint. Characterising the basis for this disruption revealed a new, pivotal stage in β-selection, bookended by up-regulation of TCR co-receptors, CD28 and CD2, respectively. Within this “DN3b Pre ” stage, CD5 and Lef1 are up-regulated to reflect pre-TCR signalling, and their expression correlates with proliferation. These findings suggest a refined model of β-selection in which a coordinated increase in expression of pre-TCR, CD28, CD5 and Lef1 allows for modulating TCR signalling strength and culminates in the expression of CD2 to enable exit from the β-selection checkpoint.
Figure S3 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532972.V1
Abstract: Supplementary Figure 3: Characterization of Pik3ca-mutated and Pten-deleted prostate hyperplasia and carcinoma. (A) IHC to detect the apoptotic marker Cleaved-Caspase-3 (CC3) in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (B) Quantitation of CC3-positive nuclei in Wt, Pik3ca+/HR and Ptenfl/fl prostate epithelium (n = 3, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test, ns = not significant. Error bars: SEM). (C) IHC to detect CK5 and CK8 in Pik3ca+/HR and Ptenfl/fl carcinomas (representative images from 3 prostates per genotype, scale bar: 50 um). (D) Representative IHC images to detect PTEN, mTORC1 signaling components (p-AKT Thr308, p-RPS6 Ser235/236 and p-4E-BP1 Thr37/46) and mTORC2 substrates (p-AKT Ser473 and p-NDRG1 Thr346) in Pik3ca+/HR and Ptenfl/fl hyperplastic lesions (n = 3, scale bar: 50 um). IHC quantitation for (E) p-AKT Thr308, (F) p-RPS6 Ser235/236, (G) p-4E-BP1 Thr37/46, (H) p-AKT Ser473 and (I) p-NDRG1 Thr346 in Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions (n = 3, Error bars: SEM, *P 0.05, unpaired, two-tailed t-test).
Vimentin Regulates Scribble Activity by Protecting It from Proteasomal Degradation
Publisher: American Society for Cell Biology (ASCB)
Date: 15-06-2009
Abstract: Scribble (Scrib), Discs large, and Lethal giant larvae form a protein complex that regulates different aspects of cell polarization, including apical–basal asymmetry in epithelial cells and anterior–posterior polarity in migrating cells. Here, we show that Scrib interacts with the intermediate filament cytoskeleton in epithelial Madin-Darby canine kidney (MDCK) cells and endothelial human umbilical vein endothelial cells. Scrib binds vimentin via its postsynaptic density 95/disc-large/zona occludens domains and in MDCK cells redistributes from filaments to the plasma membrane during the establishment of cell–cell contacts. RNA interference-mediated silencing of Scrib, vimentin, or both in MDCK cells results in defects in the polarization of the Golgi apparatus during cell migration. Concomitantly, wound healing is delayed due to the loss of directional movement. Furthermore, cell aggregation is dependent on both Scrib and vimentin. The similar phenotypes observed after silencing either Scrib or vimentin support a coordinated role for the two proteins in cell migration and aggregation. Interestingly, silencing of vimentin leads to an increased proteasomal degradation of Scrib. Thus, the upregulation of vimentin expression during epithelial to mesenchymal transitions may stabilize Scrib to promote directed cell migration.
Drosophila melanogasterGuk-holder interacts with the Scribbled PDZ1 domain and regulates epithelial development with Scribbled and Discs Large
Publisher: Elsevier BV
Date: 03-2018
E-cadherin in developing murine T cells controls spindle alignment and differentiation during β-selection
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2022
DOI: 10.1101/2022.06.14.496211
Abstract: A critical stage of T cell development is β-selection at this stage the TCRβ chain is generated and the developing T cell starts to acquire antigenic specificity. Progression through β-selection is assisted by a low affinity interaction between the nascent TCRβ chain and peptide presented on stromal MHC and external cues provided by the niche, including Notch and CXCR4. In this study, we reveal the importance of a new cue within the murine developing T cell niche which is critical for T cell development. E-cadherin mediates cell-cell interactions and influences cell fate in many developmental systems. In developing T cells E-cadherin contributed to the formation of an immunological synapse and the alignment of the mitotic spindle with the polarity axis during ision, which facilitated subsequent T cell development. Collectively, these data highlight a new aspect of the developing T cell niche and provide insights into the role of E-cadherin in the β-selection stage of T cell development.
Dissecting the role of polarity regulators in cancer through the use of mouse models.
Publisher: Elsevier BV
Date: 11-2014
A Drosophila in vivo chemical screen reveals that combination drug treatment targeting MEK and DGKα mitigates Ras-driven polarity-impaired tumourigenesis
Publisher: Cold Spring Harbor Laboratory
Date: 16-03-2022
DOI: 10.1101/2022.03.14.484232
Abstract: The RAS oncogene and upregulation of the RAS signalling pathway is highly prevalent in human cancer, and therefore, therapeutically targeting the RAS pathway is a common treatment in cancer. However, RAS pathway upregulation is not sufficient to drive malignant cancer, since senescence mechanisms prevent cancer progression. Thus, additional mutations, such as mutations that prevent senescence or alter the tissue architecture (cell polarity), are required for RAS -driven tumour progression. Moreover, targeting RAS -driven cancers with RAS pathway inhibitors can often lead to undesirable side-effects and to drug resistance. Thus, identifying compounds that synergise with RAS-pathway inhibitors would enable lower doses of the RAS pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a boutique chemical screen using a Drosophila model of Ras-driven cell polarity-impaired cancer, we have identified compounds that reduce tumour burden by synergising with subtherapeutic doses of the RAS pathway inhibitor, Trametinib, which inhibits mitogen-activated kinase kinase (MEK). Analysis of one of the hits from the screen, Ritanserin, which targets serotonin receptors and diacy glycerol kinase alpha (DGK α ), revealed that DGK α was the critical target in its synergism with Trametinib. We show that human mammary epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene, SCRIB , are also sensitive to treatment with low doses of Trametinib and DGK α inhibition. Mechanistically, DGK α inhibition synergises with Trametinib by inhibiting MEK and mTOR activity. Altogether, our results provide evidence that targeting RAS-driven human cancers with RAS pathway and DGK α inhibitors will be an effective combination therapy.
Discovery and analysis of consistent active sub-networks in cancers
Publisher: Springer Science and Business Media LLC
Date: 2013
All Known In Vivo Functions of the Oct-2 Transcription Factor Require the C-Terminal Protein Domain
Publisher: The American Association of Immunologists
Date: 03-2004
DOI: 10.4049/JIMMUNOL.172.5.2962
Abstract: Oct-2, a transcription factor expressed in the B lymphocyte lineage and in the developing CNS, functions through of a number of discrete protein domains. These include a DNA-binding POU homeodomain flanked by two transcriptional activation domains. In vitro studies have shown that the C-terminal activation domain, a serine-, threonine- and proline-rich sequence, possesses unique qualities, including the ability to activate transcription from a distance in a B cell-specific manner. In this study, we describe mice in which the endogenous oct-2 gene has been modified through gene targeting to create a mutated allele, oct-2ΔC, which encodes Oct-2 protein isoforms that lack all sequence C-terminal to the DNA-binding domain. Surprisingly, despite the retention of the DNA-binding domain and the glutamine-rich N-terminal activation domain, the truncated protein(s) encoded by the oct-2ΔC allele are unable to rescue any of the previously described defects exhibited by oct-2 null mice. Homozygous oct-2ΔC/ΔC mice die shortly after birth, and B cell maturation, B-1 cell self renewal, serum Ig levels, and B lymphocyte responses to in vitro stimulation are all reduced or absent, to a degree equivalent to that seen in oct-2 null mice. We conclude that the C-terminal activation domain of Oct-2 is required to mediate the unique and indispensable functions of the Oct-2 transcription factor in vivo.
Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity
Publisher: Impact Journals, LLC
Date: 26-11-2014
Abstract: While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.
Polarity protein scrib facilitates endothelial inflammatory signaling
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
DOI: 10.1161/ATVBAHA.115.305678
Abstract: The polarity protein Scrib is highly expressed in endothelial cells and is required for planar cell polarity. Scrib also facilitates recycling of integrin α5 to the plasma membrane. Because integrin α5 signals the presence of the inflammatory matrix protein fibronectin, we hypothesized that Scrib contributes to endothelial inflammatory signaling. Cytokine treatment of human umbilical vein endothelial cells induced an inflammatory response as evident by the induction of vascular cell adhesion molecule-1 (VCAM-1). Downregulation of Scrib greatly attenuated this effect. In endothelial-specific conditional Scrib knockout mice, in vivo lipopolysaccharide treatment resulted in an impaired VCAM-1 induction. These effects were functionally relevant because Scrib small interfering RNAs in human umbilical vein endothelial cells attenuated the VCAM-1–mediated leukocyte adhesion in response to tumor necrosis factor-α. In vivo, tamoxifen-induced endothelial-specific deletion of Scrib resulted in a reduced VCAM-1–mediated leukocyte adhesion in response to tumor necrosis factor-α in the mouse cremaster model. This effect was specific for Scrib and not mediated by other polarity proteins. Moreover, it did not involve integrin α5 or classic pathways supporting inflammatory signaling, such as nuclear factor κ light chain enhancer of activated B-cells or MAP kinases. Co-immunoprecipitation/mass spectrometry identified the zinc finger transcription factor GATA-like protein-1 as a novel Scrib interacting protein. Small interfering RNA depletion of GATA-like protein-1 decreased the tumor necrosis factor-α–stimulated VCAM-1 induction to a similar extent as loss of Scrib did. Silencing of Scrib reduced GATA-like protein-1 protein, but not mRNA abundance. Scrib is a novel proinflammatory regulator in endothelial cells, which maintains the protein expression of GATA-like protein-1.
Figure S5 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532966.V1
Abstract: Supplementary Figure 5: Pik3caH1047R mutation and Pten-deletion synergize to promote prostate cancer by increasing mTORC1/2 signaling. Histograms displaying phenotype incidence for anterior (A) and ventral (B) prostate lobes at 56 and 100 days of age. (C) Representative IHC images of Pik3ca+/HR Ptenfl/fl prostate tumors at 100 d stained to detect CK8, CK5 and SMA (n = 3, scale bar: 50 um). (D) Bar chart displaying total prostate weight normalised to body weight for Wt (n = 7), Pik3ca+/HR (n = 8), Ptenfl/fl (n = 8) and Pik3ca+/HR Ptenfl/fl (n = 7) 100 d old mice. Error bars: SEM, *P .05 compared to Wt or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Quantitation of the apoptotic marker Cleaved-Caspase-3 (CC3) positive nuclei and (F) representative IHC images of CC3 staining in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma (scale bar: 50 um, n = 3, one-way ANOVA with Tukey's multiple comparison test. Error bars: SEM). (G) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma stained to detect p-AKT Thr308, p-RPS6 Ser235/236, p-4E-BP1 Thr37/46, p-AKT Ser473 and p-NDRG1 Thr346 (scale bar: 50 um). (H) Representative images of RNA in situ hybridisation (ISH) to detect positive (housekeeping gene PPIB, peptidylprolyl isomerase B) and negative (bacterial gene dapB) control probes to confirm RNA quality and the absence of background signal respectively (scale bar: 50 um, insert scale bar: 5 um).
Cell Polarity in Motion: Redefining Mammary Tissue Organization Through EMT and Cell Polarity Transitions
Publisher: Springer Science and Business Media LLC
Date: 12-05-2010
DOI: 10.1007/S10911-010-9180-2
Abstract: Epithelial to mesenchymal transition (EMT) and its reversion via mesenchymal to epithelial transition (MET), represent a stepwise cycle of epithelial plasticity that allows for normal tissue remodelling and ersification during development. In particular, epithelial-mesenchymal plasticity is central to many aspects of mammary development and has been proposed to be a key process in breast cancer progression. Such epithelial-mesenchymal plasticity requires complex cellular reprogramming to orchestrate a change in cell shape to an alternate morphology more conducive to migration. During this process, epithelial characteristics, including apical-basal polarity and specialised cell-cell junctions are lost and mesenchymal properties, such as a front-rear polarity associated with weak cell-cell contacts, increased motility, resistance to apoptosis and invasiveness are gained. The ability of epithelial cells to undergo transitions through cell polarity states is a central feature of epithelial-mesenchymal plasticity. These cell polarity states comprise a set of distinct asymmetric distributions of cellular constituents that are fashioned to allow specialized cellular functions, such as the regulated homeostasis of molecules across epithelial barriers, cell migration or cell ersification via asymmetric cell isions. Each polarity state is engineered using a molecular toolbox that is highly conserved between organisms and cell types which can direct the initiation, establishment and continued maintenance of each asymmetry. Here we discuss how EMT pathways target cell polarity mediators, and how this EMT-dependent change in polarity states impact on the various stages of breast cancer. Emerging evidence places cell polarity at the interface of proliferation and morphology control and as such the changing dynamics within polarity networks play a critical role in normal mammary gland development and breast cancer progression.
Scribble acts as an oncogene in Eμ-myc-driven lymphoma
Publisher: Springer Science and Business Media LLC
Date: 18-05-2015
DOI: 10.1038/ONC.2015.167
Abstract: Scribble complex proteins maintain apicobasal polarity, regulate cell fate determination and function as tumour suppressors in epithelial tissue. Despite evidence that the function of Scribble is maintained in the lymphocyte lineage, we still understand little about its role as a tumour suppressor in haematological malignancies. Using the Eμ-myc model of Burkitt's lymphoma we investigated the role of Scribble in lymphomagenesis. We found that contrary to its well-documented tumour suppressor role in epithelial tissue, loss of Scribble expression delayed the expansion of peripheral B cells and delayed the onset of Eμ-myc-driven lymphoma. This was despite upregulated ERK phosphorylation levels in Scribble-deficient tumours, which are associated with loss of Scribble expression and the development of more aggressive Burkitt's lymphoma. Interestingly, the developmental stage of lymphoma was unaffected by Scribble expression challenging any role for Scribble in fate determination in the haematopoetic lineage. These data provide evidence for oncogenic properties of Scribble in Myc-driven B-cell lymphomagenesis, reinforcing recent findings that overexpression of a mutant form of Scribble can act as an oncogene in epithelial cells. Our results support the growing appreciation that the tumour regulatory functions of Scribble, and other polarity protein family members, are context dependent.
The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge
Publisher: Springer Science and Business Media LLC
Date: 09-10-2007
Abstract: Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.
A Scribble-E-cadherin complex controls daughter cell patterning by multiple mechanisms
Publisher: Cold Spring Harbor Laboratory
Date: 16-04-2021
DOI: 10.1101/2021.04.15.440081
Abstract: The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate patterning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble, links E-cadherin to NuMA and Arp2/3 signalling for sequential roles in daughter positioning. First Scribble transmits cues from E-cadherin localised in retraction fibres to control orientation of the mitotic spindle. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter-daughter junction, generation of filopodia and subsequent cell patterning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell ision to orient the mitotic spindle and control placement of the daughter cells after cell ision.
Figure S4 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532969.V1
Abstract: Supplementary Figure 4: Pik3caH1047R heterozygous oncogenic mutation causes p110alpha-dependent prostate cancer. Representative H& E images (scale bar: 100 um) for Pik3ca+/HR and Ptenfl/fl dorsolateral prostate and histograms displaying phenotype incidence for anterior (B) and ventral (C) prostate lobes from Pik3ca+/HR and Ptenfl/fl mice treated with vehicle, p110alpha�inhibitor (A66), p110beta inhibitor (TGX-221), pan-PI3K inhibitor (BKM120) or A66 + TGX-221 for 4 weeks. ND = not done. A66 and TGX-221 were generated in house by P.R.S. (University of Auckland, New Zealand) (14) and BKM120 was obtained from SYNkinase (Australia).
E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation
Publisher: American Society of Hematology
Date: 08-2006
DOI: 10.1182/BLOOD-2005-09-008656
Abstract: The E2F proteins are major regulators of the transcriptional program required to coordinate cell cycle progression and exit. In particular, E2f4 has been proposed to be the principal family member responsible for the regulation of cell cycle exit chiefly through its transcriptional repressive properties. We have previously shown that E2f4–/– mice display a marked macrocytic anemia implicating E2f4 in the regulation of erythropoiesis. However, these studies could not distinguish whether E2f4 was required for differentiation, survival, or proliferation control. Here, we describe a novel function for E2f4 in the promotion of erythroid proliferation. We show that loss of E2f4 results in an impaired expansion of the fetal erythroid compartment in vivo that is associated with impaired cell cycle progression and decreased erythroid proliferation. Consistent with these observations, cDNA microarray analysis reveals cell cycle control genes as one of the major class of genes down-regulated in E2f4–/– FLs, and we provide evidence that E2f4 may directly regulate the transcriptional expression of a number of these genes. We conclude that the macrocytic anemia of E2f4–/– mice results primarily from impaired cellular proliferation and that the major role of E2f4 in fetal erythropoiesis is to promote cell cycle progression and cellular proliferation.
E-cadherin in developing murine T cells controls spindle alignment and progression through β-selection
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-01-2023
Abstract: A critical stage of T cell development is β-selection at this stage, the T cell receptor β (TCRβ) chain is generated, and the developing T cell starts to acquire antigenic specificity. Progression through β-selection is assisted by low-affinity interactions between the nascent TCRβ chain and peptide presented on stromal major histocompatibility complex and cues provided by the niche. In this study, we identify a cue within the developing T cell niche that is critical for T cell development. E-cadherin mediates cell-cell interactions and influences cell fate in many developmental systems. In developing T cells, E-cadherin contributed to the formation of an immunological synapse and the alignment of the mitotic spindle with the polarity axis during ision, which facilitated subsequent T cell development. Collectively, these data suggest that E-cadherin facilitates interactions with the thymic niche to coordinate the β-selection stage of T cell development.
Figure S2 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532975.V1
Abstract: Supplementary Figure 2: Heterozygous Pik3caH1047R oncogenic mutation causes invasive prostate cancer in mice that is phenotypically distinct to Pten-null prostate cancer. (A) Sequencing cDNA isolated from PBiCre+/- Pik3ca+/HR prostate tissue confirmed heterozygosity at known silent base changes within mutant exon 20 adjacent to exon 19, indicating recombination has occurred. (B) allele-specific PCR of cDNA isolated from PBiCre+/- prostate tissue expressing either Pik3ca+/+ (Wt) or Pik3ca+/HR alleles (as previously described (13)) revealed the presence of the mutant exon 20 in PBiCre+/- Pik3ca+/HR prostate cDNA, but not in PBiCre+/- Wt prostate cDNA. (C) Representative H& E images of PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral and anterior prostate epithelium at 400 d (scale bar: 100 um). Phenotype incidence plots for PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral (D) and anterior (E) prostate lobes. VP = Ventral prostate, AP = anterior prostate, PIN = prostate intraepithelial neoplasia. (F) IHC to detect SMA in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (G) Quantitation of PCNA-positive nuclei in PBiCre+/- Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions. *P .001, one-way ANOVA with Tukey's multiple comparison test, n = 3. Error bars: SEM.
Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration
Publisher: Frontiers Media SA
Date: 18-08-2022
DOI: 10.3389/FPSYT.2022.958688
Abstract: Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.
Scribble Interacts with β-Catenin to Localize Synaptic Vesicles to Synapses
Publisher: American Society for Cell Biology (ASCB)
Date: 15-07-2009
Abstract: An understanding of how synaptic vesicles are recruited to and maintained at presynaptic compartments is required to discern the molecular mechanisms underlying presynaptic assembly and plasticity. We have previously demonstrated that cadherin–β-catenin complexes cluster synaptic vesicles at presynaptic sites. Here we show that scribble interacts with the cadherin–β-catenin complex to coordinate vesicle localization. Scribble and β-catenin are colocalized at synapses and can be coimmunoprecipitated from neuronal lysates, indicating an interaction between scribble and β-catenin at the synapse. Using an RNA interference approach, we demonstrate that scribble is important for the clustering of synaptic vesicles at synapses. Indeed, in scribble knockdown cells, there is a diffuse distribution of synaptic vesicles along the axon, and a deficit in vesicle recycling. Despite this, synapse number and the distribution of the presynaptic active zone protein, bassoon, remain unchanged. These effects largely phenocopy those observed after ablation of β-catenin. In addition, we show that loss of β-catenin disrupts scribble localization in primary neurons but that the localization of β-catenin is not dependent on scribble. Our data supports a model by which scribble functions downstream of β-catenin to cluster synaptic vesicles at developing synapses.
Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2018
DOI: 10.1158/2159-8290.CD-17-0867
Abstract: Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/ lification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in vivo. Furthermore, we report that PIK3CA mutation and PTEN loss coexist in patients with prostate cancer and can cooperate in vivo to accelerate disease progression via AKT–mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients. Significance: We show PIK3CA mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover, PIK3CA mutation and PTEN loss coexist in prostate cancer and can cooperate in vivo to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic rognostic approaches to overcome castration/PI3K–AKT–mTORC1/2 inhibitor resistance. Cancer Discov 8(6) 764–79. ©2018 AACR. See related commentary by Triscott and Rubin, p. 682. This article is highlighted in the In This Issue feature, p. 663
PTPN2 elicits cell autonomous and non–cell autonomous effects on antitumor immunity in triple-negative breast cancer
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-02-0033
Abstract: The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1–dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.
Supplemetary Material and Tables from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progre
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532957
Abstract: Supplemetary Material and Tables S1 - S7
Lethal Giant Larvae 1 Tumour Suppressor Activity Is Not Conserved in Models of Mammalian T and B Cell Leukaemia
Publisher: Public Library of Science (PLoS)
Date: 27-01-2014
Figure S7 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532960
Abstract: Supplementary Figure 7: Characterization of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tumors. Representative images of IHC to detect (A) PCNA and (B) Cleaved-caspase 3 (CC3) in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl =100 d old. Quantitative RT-PCR to detect (C) Nkx3.1 and (D) Pbsn mRNA in Wt prostate and Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched prostate carcinomas (n = 5). Error bars: SEM, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Western Blotting of protein lysates isolated from Wt prostate and stage-matched Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate carcinomas to detect total AKT, p-AKT Thr308 and p-AKT Ser473 (n = 3).
Cell Polarity Regulation—From Atomic to Macroscopic Scale
Publisher: Elsevier BV
Date: 09-2018
Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species
Publisher: Springer Science and Business Media LLC
Date: 05-06-2017
DOI: 10.1038/ONC.2017.175
Abstract: Activation of Ras signalling occurs in ~30% of human cancers however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras ( Ras V12 ) in Drosophila , we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP , correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances Ras V12 -driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in Ras V12 clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers.
SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
Publisher: American Society for Clinical Investigation
Date: 11-2011
DOI: 10.1172/JCI58509
Correction: TSPAN6 is a suppressor of Ras-driven cancer
Publisher: Springer Science and Business Media LLC
Date: 15-03-2022
Intermittent hypoxia induces a metastatic phenotype in breast cancer
Publisher: Springer Science and Business Media LLC
Date: 05-2018
DOI: 10.1038/S41388-018-0259-3
Abstract: Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal ersity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.
Figure S1 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532978.V1
Abstract: Supplementary Figure 1: PIK3CA mutations are predominantly missense mutations and PTEN mutation/loss predicts for poor prostate cancer patient survival. (A) Pie chart depicting the frequency of missense/nonsense mutations, in-frame deletions and fusion events in PIK3CA identified in the 9 prostate cancer genomic datasets assessed in Fig. 1A (3-10). (B) Kaplan-Meier plot comparing TCGA provisional prostate adenocarcinoma dataset with PTEN homozygous deletion, loss or mutation compared to the general population. PTEN age-adjusted COXPH HR: 0.47, P = 0.0026* (n = 492, s les with sequencing and CNA data only). Data was obtained from the TCGA data portal (tcga-data.nci.nih.gov/). PTEN copy number loss criteria Log R ratio {less than or equal to} -0.48, probe number {greater than or equal to} 10. Silent mutations were excluded.
Mitotic Spindle Orientation: Semaphorin-Plexin Signaling Flags the Way
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.DEVCEL.2015.04.012
Abstract: The extracellular signals and corresponding receptors that align the mitotic spindle of symmetrically iding cells within an epithelial sheet are largely unknown. In this issue of Developmental Cell, Xia et al. (2015) identify semaphorin-plexin signaling as a regulator of spindle orientation critical for kidney development and repair.
Multiscale Modeling of Form and Function
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-04-2009
Abstract: Topobiology posits that morphogenesis is driven by differential adhesive interactions among heterogeneous cell populations. This paradigm has been revised to include force-dependent molecular switches, cell and tissue tension, and reciprocal interactions with the microenvironment. It is now appreciated that tissue development is executed through conserved decision-making modules that operate on multiple length scales from the molecular and subcellular level through to the cell and tissue level and that these regulatory mechanisms specify cell and tissue fate by modifying the context of cellular signaling and gene expression. Here, we discuss the origin of these decision-making modules and illustrate how emergent properties of adhesion-directed multicellular structures sculpt the tissue, promote its functionality, and maintain its homeostasis through spatial segregation and organization of anchored proteins and secreted factors and through emergent properties of tissues, including tension fields and energy optimization.
Figure S4 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532969
Abstract: Supplementary Figure 4: Pik3caH1047R heterozygous oncogenic mutation causes p110alpha-dependent prostate cancer. Representative H& E images (scale bar: 100 um) for Pik3ca+/HR and Ptenfl/fl dorsolateral prostate and histograms displaying phenotype incidence for anterior (B) and ventral (C) prostate lobes from Pik3ca+/HR and Ptenfl/fl mice treated with vehicle, p110alpha�inhibitor (A66), p110beta inhibitor (TGX-221), pan-PI3K inhibitor (BKM120) or A66 + TGX-221 for 4 weeks. ND = not done. A66 and TGX-221 were generated in house by P.R.S. (University of Auckland, New Zealand) (14) and BKM120 was obtained from SYNkinase (Australia).
Loss of APKC expression independently predicts tumor recurrence in superficial bladder cancers
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.UROLONC.2011.03.012
Abstract: Epithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. Our aim was to investigate the role of tight junction proteins, Par3/Par6/atypical protein kinase C (APKC), Discs large (Dlg), and Scribble in human bladder pathogenesis. We evaluated levels of APKC, Dlg, and Scribble in 92 superficial bladder tumors using tissue microarrays and immunohistochemistry, and correlated expression with pathologic variables and clinical outcomes. There was a slight apparent enrichment in strong vs. weak staining for APKC (54.9% vs. 45.1%), Dlg (65.7% vs. 34.3%), and a marked enrichment for Scribble (75% vs. 25%) in the superficial bladder tumors. Univariate analysis determined that both tumor focality and APKC expression were significantly associated with tumor recurrence (P < 0.05). Multivariate analysis using the Cox's proportional hazards model revealed that only APKC (P = 0.025) as well as tumor focality (P = 0.018) were independent and significant prognostic factors for tumor recurrence in all patients. We found that no immunohistochemical staining of any of the cell polarity proteins significantly predicted for tumor progression on either univariate or multivariate analysis. Loss of APKC expression in superficial bladder tumors is a strong predictor of tumor recurrence.
Calcium Signaling Is Required for Erythroid Enucleation
Publisher: Public Library of Science (PLoS)
Date: 05-01-2016
The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis
Publisher: Springer Science and Business Media LLC
Date: 17-09-2015
Figure S5 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532966
Abstract: Supplementary Figure 5: Pik3caH1047R mutation and Pten-deletion synergize to promote prostate cancer by increasing mTORC1/2 signaling. Histograms displaying phenotype incidence for anterior (A) and ventral (B) prostate lobes at 56 and 100 days of age. (C) Representative IHC images of Pik3ca+/HR Ptenfl/fl prostate tumors at 100 d stained to detect CK8, CK5 and SMA (n = 3, scale bar: 50 um). (D) Bar chart displaying total prostate weight normalised to body weight for Wt (n = 7), Pik3ca+/HR (n = 8), Ptenfl/fl (n = 8) and Pik3ca+/HR Ptenfl/fl (n = 7) 100 d old mice. Error bars: SEM, *P .05 compared to Wt or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Quantitation of the apoptotic marker Cleaved-Caspase-3 (CC3) positive nuclei and (F) representative IHC images of CC3 staining in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma (scale bar: 50 um, n = 3, one-way ANOVA with Tukey's multiple comparison test. Error bars: SEM). (G) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma stained to detect p-AKT Thr308, p-RPS6 Ser235/236, p-4E-BP1 Thr37/46, p-AKT Ser473 and p-NDRG1 Thr346 (scale bar: 50 um). (H) Representative images of RNA in situ hybridisation (ISH) to detect positive (housekeeping gene PPIB, peptidylprolyl isomerase B) and negative (bacterial gene dapB) control probes to confirm RNA quality and the absence of background signal respectively (scale bar: 50 um, insert scale bar: 5 um).
Figure S6 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532963
Abstract: Supplementary Figure 6: Pik3ca+/HR and Ptenfl/fl prostate cancers acquire CRPC, while Pik3ca+/HR Ptenfl/fl mutants are resistant to castration. (A) Representative H& E images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl anterior (AP) and ventral (VP) prostate lobes post-castration (scale bar: 50 um, n = 3). (B) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue stained to detect Androgen receptor (AR) 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl = 100 d old. Insert displays positive AR nuclei (arrows) in Pik3ca+/HR Ptenfl/fl compound mutants (scale bar: 5 um). (C) Bar chart displaying total prostate weight normalised to body weight for Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (n = 8, 7 and 7, respectively). Error bars: SEM, *P .05 compared to 0 weeks post-castration, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (D) Representative H& E images of Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (scale bar: 100 um). Mice were castrated at 100 d of age.
hScrib is a functional homologue of the Drosophila tumour suppressor Scribble
Publisher: Springer Science and Business Media LLC
Date: 18-12-2003
Polarity Regulators and the Control of Epithelial Architecture, Cell Migration, and Tumorigenesis
Publisher: Elsevier
Date: 2007
The cell adhesion receptor TMIGD1 recruits Scribble to the basolateral membrane via direct interaction
Publisher: Research Square Platform LLC
Date: 16-03-2023
DOI: 10.21203/RS.3.RS-2639220/V1
Abstract: Scribble (Scrib) is a multidomain polarity protein and member of the leucine-rich repeat (LRR) and PDZ domain (LAP) protein family. A loss of Scrib expression is associated with disturbed apical-basal polarity and tumor formation. The tumor suppressive activity of Scrib depends on its membrane localization. However, despite the identification of numerous Scrib-interacting proteins, the mechanisms regulating its membrane recruitment are unclear. Here, we identify the cell adhesion receptor TMIGD1 as a membrane anchor of Scrib. TMIGD1 directly interacts with Scrib through a PDZ domain-mediated interaction. We characterize the association of the TMIGD1 C-terminus with each Scrib PDZ domain and describe the crystal structure of the TMIGD1 peptide – Scrib PDZ1 complex. We also find that TMIGD1 recruits Scrib to the lateral membrane domain when the LRR region is absent. Our findings describe a mechanism of Scrib membrane localization and contribute to the understanding of the tumor suppressive activity of Scrib.
A Phenotypic High-Content Screening Assay to Identify Regulators of Membrane Protein Localization
Publisher: Mary Ann Liebert Inc
Date: 10-2016
DOI: 10.1089/ADT.2016.733
Abstract: Correct subcellular localization of proteins is a requirement for appropriate function. This is especially true in epithelial cells, which rely on the precise localization of a erse array of epithelial polarity and cellular adhesion proteins. Loss of cell polarity and adhesion is a hallmark of cancer, and mislocalization of core polarity proteins, such as Scribble, is observed in a range of human epithelial tumors and is prognostic of poor survival. Despite this, little is known about how Scribble membrane localization is regulated. Here, we describe the development and application of a phenotypic high-content screening assay that is designed to specifically quantify membrane levels of Scribble to identify regulators of its membrane localization. A screening platform that is capable of resolving in idual cells and quantifying membrane protein localization in confluent epithelial monolayers was developed by using the cytoplasm-to-cell-membrane bioapplication integrated with the Cellomics ArrayScan high-content imaging platform. Application of this method to a boutique human epithelial polarity and signaling small interfering RNA (siRNA) library resulted in highly robust coefficient-of-variance and Z' factor values. As proof of concept, we present two candidate genes whose depletion specifically reduces Scribble protein levels at the membrane. Data mining revealed that these proteins interact with components of the Scribble polarity complex, providing support for the utility of the screening approach. This method is broadly applicable to genome-wide and large-scale compound screening of membrane-bound proteins, and when coupled with pathway analysis the dataset becomes even more valuable and can provide predictive mechanistic insight.
New tricks for old dogs: Unexpected roles for cell cycle regulators revealed using animal models
Publisher: Elsevier BV
Date: 12-2004
TSPAN6 is a suppressor of Ras-driven cancer
Publisher: Springer Science and Business Media LLC
Date: 19-02-2022
DOI: 10.1038/S41388-022-02223-Y
Abstract: Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer genes that affect Ras-driven tumorigenesis and metastasis in Drosophila including confirmation of the tetraspanin Tsp29Fb. However, it was not known whether the mammalian Tsp29Fb orthologue, TSPAN6, has any role in RAS-driven human epithelial tumors. Here we show that TSPAN6 suppressed tumor growth and metastatic dissemination of human RAS activating mutant pancreatic cancer xenografts. Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced Kras G12D -driven lung tumor initiation and malignant progression. Mechanistically, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation. Moreover, we show that inactivation of TSPAN6 induces an epithelial-to-mesenchymal transition and inhibits cell migration in vitro and in vivo. Finally, low TSPAN6 expression correlates with poor prognosis of patients with lung and pancreatic cancers with mesenchymal morphology. Our results uncover TSPAN6 as a novel tumor suppressor receptor that controls epithelial cell identify and restrains RAS-driven epithelial cancer.
Structural analysis of phosphorylation-associated interactions of human MCC with Scribble PDZ domains.
Publisher: Wiley
Date: 30-07-2019
DOI: 10.1111/FEBS.15002
Abstract: Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbours a leucine-rich repeat domain and four PDZ domains that mediate most of Scribble's interactions with other proteins. It has become increasingly clear that post-translational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated human Scribble interactions with MCC (Mutated in Colorectal Cancer). We systematically evaluated the ability of all four in idual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a minor effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the unphosphorylated MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC must extend beyond a simple modulation of the affinity for Scribble PDZ domains.
TIME-Seq Enables Scalable and Inexpensive Epigenetic Age Predictions
Publisher: Cold Spring Harbor Laboratory
Date: 28-10-2021
DOI: 10.1101/2021.10.25.465725
Abstract: Epigenetic “clocks” based on DNA methylation (DNAme) have emerged as the most robust and widely employed aging biomarkers, but conventional methods for applying them are expensive and laborious. Here, we develop T agmentation-based Indexing for M ethylation Seq uencing (TIME-Seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-Seq, we applied multi-tissue and tissue-specific epigenetic clocks to over 1,600 mouse DNA s les. We also discovered a novel approach for age prediction from shallow sequencing (e.g., 10,000 reads) by adapting scAge for bulk measurements. In benchmarking experiments, TIME-Seq performed favorably against prevailing methods and could quantify the effects of interventions thought to accelerate, slow, and reverse aging in mice. Finally, we built and validated a highly accurate human blood clock from 1,056 demographically representative in iduals. Our methods increase the scalability and reduce the cost of epigenetic age predictions by more than 100-fold, enabling accurate aging biomarkers to be applied in more large-scale animal and human studies.
A Chemical Screening Approach to Identify Novel Key Mediators of Erythroid Enucleation
Publisher: Public Library of Science (PLoS)
Date: 16-11-2015
Scribble regulates an EMT–polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/JCS.129387
Abstract: The crucial role the Crumbs and Par polarity complexes play in tight junction integrity has long been established, however very few studies have investigated the role of the Scribble polarity module. Here we use MCF10A cells, which fail to form tight junctions and express very little endogenous Crumbs3, to show that inducing expression of the polarity protein Scribble is sufficient to promote tight junction formation. We show this occurs through an epithelial to mesenchymal (EMT) pathway that involves Scribble suppressing ERK phosphorylation, leading to down regulation of the EMT inducer ZEB. Inhibition of ZEB relieves the repression on Crumbs3, resulting in increased expression of this crucial tight junction regulator. The combined effect of this Scribble mediated pathway is the upregulation of a number of junctional proteins and the formation of functional tight junctions. These data suggests a novel role for Scribble in positively regulating tight junction assembly through transcriptional regulation of an EMT signaling program.
Figure S1 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532978
Abstract: Supplementary Figure 1: PIK3CA mutations are predominantly missense mutations and PTEN mutation/loss predicts for poor prostate cancer patient survival. (A) Pie chart depicting the frequency of missense/nonsense mutations, in-frame deletions and fusion events in PIK3CA identified in the 9 prostate cancer genomic datasets assessed in Fig. 1A (3-10). (B) Kaplan-Meier plot comparing TCGA provisional prostate adenocarcinoma dataset with PTEN homozygous deletion, loss or mutation compared to the general population. PTEN age-adjusted COXPH HR: 0.47, P = 0.0026* (n = 492, s les with sequencing and CNA data only). Data was obtained from the TCGA data portal (tcga-data.nci.nih.gov/). PTEN copy number loss criteria Log R ratio {less than or equal to} -0.48, probe number {greater than or equal to} 10. Silent mutations were excluded.
Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: a RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis.
Publisher: Oxford University Press (OUP)
Date: 05-2011
DOI: 10.1534/GENETICS.111.127910
Abstract: We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (RasACT) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with RasACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance RasACT-driven hyperplasia. RasACT-cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wild-type cells, only Rac1, an activated allele of Rho1 (Rho1ACT), RhoGEF2, and pbl cooperated with RasACT, resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with RasACT upregulated Jun kinase (JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with RasACT, while in the clonal setting, JNK upregulation was sufficient for RasACT-mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of RasV12-expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2+ human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with RasACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/Rho-family/JNK pathway in cooperative tumorigenesis with RasACT.
Figure S3 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532972
Abstract: Supplementary Figure 3: Characterization of Pik3ca-mutated and Pten-deleted prostate hyperplasia and carcinoma. (A) IHC to detect the apoptotic marker Cleaved-Caspase-3 (CC3) in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (B) Quantitation of CC3-positive nuclei in Wt, Pik3ca+/HR and Ptenfl/fl prostate epithelium (n = 3, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test, ns = not significant. Error bars: SEM). (C) IHC to detect CK5 and CK8 in Pik3ca+/HR and Ptenfl/fl carcinomas (representative images from 3 prostates per genotype, scale bar: 50 um). (D) Representative IHC images to detect PTEN, mTORC1 signaling components (p-AKT Thr308, p-RPS6 Ser235/236 and p-4E-BP1 Thr37/46) and mTORC2 substrates (p-AKT Ser473 and p-NDRG1 Thr346) in Pik3ca+/HR and Ptenfl/fl hyperplastic lesions (n = 3, scale bar: 50 um). IHC quantitation for (E) p-AKT Thr308, (F) p-RPS6 Ser235/236, (G) p-4E-BP1 Thr37/46, (H) p-AKT Ser473 and (I) p-NDRG1 Thr346 in Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions (n = 3, Error bars: SEM, *P 0.05, unpaired, two-tailed t-test).
Figure S2 from Identification of <i>Pik3ca</i> Mutation as a Genetic Driver of Prostate Cancer That Cooperates with <i>Pten</i> Loss to Accelerate Progression and Castration-Re
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532975
Abstract: Supplementary Figure 2: Heterozygous Pik3caH1047R oncogenic mutation causes invasive prostate cancer in mice that is phenotypically distinct to Pten-null prostate cancer. (A) Sequencing cDNA isolated from PBiCre+/- Pik3ca+/HR prostate tissue confirmed heterozygosity at known silent base changes within mutant exon 20 adjacent to exon 19, indicating recombination has occurred. (B) allele-specific PCR of cDNA isolated from PBiCre+/- prostate tissue expressing either Pik3ca+/+ (Wt) or Pik3ca+/HR alleles (as previously described (13)) revealed the presence of the mutant exon 20 in PBiCre+/- Pik3ca+/HR prostate cDNA, but not in PBiCre+/- Wt prostate cDNA. (C) Representative H& E images of PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral and anterior prostate epithelium at 400 d (scale bar: 100 um). Phenotype incidence plots for PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral (D) and anterior (E) prostate lobes. VP = Ventral prostate, AP = anterior prostate, PIN = prostate intraepithelial neoplasia. (F) IHC to detect SMA in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (G) Quantitation of PCNA-positive nuclei in PBiCre+/- Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions. *P .001, one-way ANOVA with Tukey's multiple comparison test, n = 3. Error bars: SEM.
Scribble and E-cadherin cooperate to control symmetric daughter cell positioning by multiple mechanisms
Publisher: The Company of Biologists
Date: 15-01-2023
DOI: 10.1242/JCS.260547
Abstract: The fate of the two daughter cells is intimately connected to their positioning, which is in turn regulated by cell junction remodelling and orientation of the mitotic spindle. How multiple cues are integrated to dictate the ultimate positioning of daughters is not clear. Here, we identify novel mechanisms of regulation of daughter positioning in single MCF10A cells. The polarity protein, Scribble cooperates with E-cadherin for sequential roles in daughter positioning. First Scribble stabilises E-cadherin at the mitotic cortex as well as the retraction fibres, to mediate spindle orientation. Second, Scribble re-locates to the junction between the two daughters to allow a new E-cadherin-based-interface to form between them, influencing the width of the nascent daughter–daughter junction and subsequent cell positioning. Thus, E-cadherin and Scribble dynamically relocate to different intracellular sites during cell ision to orient the mitotic spindle and control placement of the daughter cells after cell ision. This article has an associated First Person interview with the first author of the paper.
Structural basis for the differential interaction of Scribble PDZ domains with the guanine nucleotide exchange factor β-PIX
Publisher: Elsevier BV
Date: 12-2017
Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1
Publisher: Springer Science and Business Media LLC
Date: 10-07-2023
DOI: 10.1038/S42003-023-05088-3
Abstract: Scribble (Scrib) is a multidomain polarity protein and member of the leucine-rich repeat and PDZ domain (LAP) protein family. A loss of Scrib expression is associated with disturbed apical-basal polarity and tumor formation. The tumor-suppressive activity of Scrib correlates with its membrane localization. Despite the identification of numerous Scrib-interacting proteins, the mechanisms regulating its membrane recruitment are not fully understood. Here, we identify the cell adhesion receptor TMIGD1 as a membrane anchor of Scrib. TMIGD1 directly interacts with Scrib through a PDZ domain-mediated interaction and recruits Scrib to the lateral membrane domain in epithelial cells. We characterize the association of TMIGD1 with each Scrib PDZ domain and describe the crystal structure of the TMIGD1 C-terminal peptide complexed with PDZ domain 1 of Scrib. Our findings describe a mechanism of Scrib membrane localization and contribute to the understanding of the tumor-suppressive activity of Scrib.
A Network of PDZ-Containing Proteins Regulates T Cell Polarity and Morphology during Migration and Immunological Synapse Formation
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.IMMUNI.2005.04.009
Abstract: T cell shape is dictated by the selective recruitment of molecules to different regions of the cell (polarity) and is integral to every aspect of T cell function, from migration to cytotoxicity. This study describes a mechanism for the regulation of T cell polarity. We show that T cells contain a network of asymmetrically distributed proteins with the capacity to dictate the subcellular localization of both cell surface receptors and morphological determinants in T cells. Proteins from the Scribble, Crumbs3, and Par3 complexes, previously shown to regulate epithelial polarity, were polarized in T cells containing either uropods or immunological synapses. Reduction in Scribble expression prevented the polarization of cell surface receptors and prevented morphological changes associated with uropod formation, migration, and antigen presentation. By dynamically coordinating molecular distribution throughout the T cell, this network provides a mechanism by which T cell function and polarity are linked.
Keratin 76 is required for tight junction function and maintenance of the skin barrier.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2014
RNAi-Mediated Knock-Down of Arylamine N-acetyltransferase-1 Expression Induces E-cadherin Up-Regulation and Cell-Cell Contact Growth Inhibition
Publisher: Public Library of Science (PLoS)
Date: 09-02-2011
Guest Editors
Publisher: Springer Science and Business Media LLC
Date: 24-11-2008
DOI: 10.1038/ONC.2008.338
On the guardians of polarity and the disorientation of cancer
Publisher: Springer Science and Business Media LLC
Date: 24-11-2008
DOI: 10.1038/ONC.2008.339
EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2
Publisher: Elsevier BV
Date: 07-2009
Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling
Publisher: Springer Science and Business Media LLC
Date: 21-07-2008
DOI: 10.1038/ONC.2008.219
Abstract: Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.
Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo
Publisher: Springer Science and Business Media LLC
Date: 25-11-2013
DOI: 10.1038/ONC.2013.498
Abstract: Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib(+/-) mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRas(G12D) murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRas(G12D) lung tumors following Scrib loss.
Related Organisations
Massachusetts Institute Of Technology
Location: United States of America
Walter And Eliza Hall Institute Of Medical Research
Location: Australia
Related Funding Activities
Discovery Projects - Grant ID: DP190103634
Start Date: 09-2019
End Date: 12-2023
Amount: $507,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE220100185
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End Date: 12-2022
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View Funded ActivityDiscovery Projects - Grant ID: DP170102549
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End Date: 03-2020
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