ORCID Profile
0000-0002-4687-629X
Current Organisations
The Francis Crick Institute
,
Barts Cancer Institute
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Related Links
Publications
Regulation of the cytokinesis cleavage furrow by PKCε
Publisher: Portland Press Ltd.
Date: 17-11-2014
DOI: 10.1042/BST20140240
Abstract: Cytokinesis is the final act of the cell cycle where the replicated DNA and cellular contents are finally split into two daughter cells. This process is very tightly controlled as DNA segregation errors and cytokinesis failure is commonly associated with aneuploidy and aggressive tumours. Protein kinase Cε (PKCε) is a lipid-activated serine/threonine kinase that is part of the PKC superfamily. PKCε plays a complex role in the regulation of migration, adhesion and cytokinesis and in the present article we discuss the interplay between these processes. Integrin-mediated interaction with the actin cytoskeleton is a known regulator of cell adhesion and migration and there is emerging evidence that this pathway may also be essential for cytokinesis. We discuss evidence that a known actin-binding region in PKCε is involved in PKCε-mediated regulation of cytokinesis, providing a link between integrin-mediated stabilization of the cytokinesis furrow and PKCε recruitment.
Equivocal, explicit and emergent actions of PKC isoforms in cancer
Publisher: Springer Science and Business Media LLC
Date: 11-11-2020
DOI: 10.1038/S41568-020-00310-4
Abstract: The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
Data from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512023.V1
Abstract: Abstract Chromosomal instability (CIN) comprises continual gain and loss of chromosomes or parts of chromosomes and occurs in the majority of cancers, often conferring poor prognosis. Because of a scarcity of functional studies and poor understanding of how genetic or gene expression landscapes connect to specific CIN mechanisms, causes of CIN in most cancer types remain unknown. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynecologic malignancy in the Western world, with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosomal aberrations and knowledge of causative mechanisms would represent an important step toward combating this disease. Here we perform the first in-depth functional characterization of mechanisms driving CIN in HGSC in seven cell lines that accurately recapitulate HGSC genetics. Multiple mechanisms coexisted to drive CIN in HGSC, including elevated microtubule dynamics and DNA replication stress that can be partially rescued to reduce CIN by low doses of paclitaxel and nucleoside supplementation, respectively. Distinct CIN mechanisms indicated relationships with HGSC-relevant therapy including PARP inhibition and microtubule-targeting agents. Comprehensive genomic and transcriptomic profiling revealed deregulation of various genes involved in genome stability but were not directly predictive of specific CIN mechanisms, underscoring the importance of functional characterization to identify causes of CIN. Overall, we show that HGSC CIN is complex and suggest that specific CIN mechanisms could be used as functional biomarkers to indicate appropriate therapy. Significance: These findings characterize multiple deregulated mechanisms of genome stability that lead to CIN in ovarian cancer and demonstrate the benefit of integrating analysis of said mechanisms into predictions of therapy response. /
Data from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512023
Abstract: Abstract Chromosomal instability (CIN) comprises continual gain and loss of chromosomes or parts of chromosomes and occurs in the majority of cancers, often conferring poor prognosis. Because of a scarcity of functional studies and poor understanding of how genetic or gene expression landscapes connect to specific CIN mechanisms, causes of CIN in most cancer types remain unknown. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynecologic malignancy in the Western world, with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosomal aberrations and knowledge of causative mechanisms would represent an important step toward combating this disease. Here we perform the first in-depth functional characterization of mechanisms driving CIN in HGSC in seven cell lines that accurately recapitulate HGSC genetics. Multiple mechanisms coexisted to drive CIN in HGSC, including elevated microtubule dynamics and DNA replication stress that can be partially rescued to reduce CIN by low doses of paclitaxel and nucleoside supplementation, respectively. Distinct CIN mechanisms indicated relationships with HGSC-relevant therapy including PARP inhibition and microtubule-targeting agents. Comprehensive genomic and transcriptomic profiling revealed deregulation of various genes involved in genome stability but were not directly predictive of specific CIN mechanisms, underscoring the importance of functional characterization to identify causes of CIN. Overall, we show that HGSC CIN is complex and suggest that specific CIN mechanisms could be used as functional biomarkers to indicate appropriate therapy. Significance: These findings characterize multiple deregulated mechanisms of genome stability that lead to CIN in ovarian cancer and demonstrate the benefit of integrating analysis of said mechanisms into predictions of therapy response. /
Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development
Publisher: Wiley
Date: 2008
DOI: 10.1002/GCC.20552
Abstract: Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways.
Data from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513834.V1
Abstract: Abstract Topoisomerase 2a (Topo2a)-dependent G sub /sub arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G sub /sub arrest by determining that p53–p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G sub /sub arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G sub /sub arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G sub /sub arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention. Significance: The identification of a requirement for p53 in stringent Topo2a-dependent G sub /sub arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality. /
Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431180.V1
Abstract: Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
PKCɛ switches Aurora B specificity to exit the abscission checkpoint
Publisher: Springer Science and Business Media LLC
Date: 22-12-2016
DOI: 10.1038/NCOMMS13853
Abstract: The ‘NoCut’, or Aurora B abscission checkpoint can be activated if DNA is retained in the cleavage furrow after completion of anaphase. Checkpoint failure leads to incomplete abscission and a binucleate outcome. These phenotypes are also observed after loss of PKCɛ in transformed cell models. Here we show that PKCɛ directly modulates the Aurora B-dependent abscission checkpoint by phosphorylating Aurora B at S227. This phosphorylation invokes a switch in Aurora B specificity, with increased phosphorylation of a subset of target substrates, including the CPC subunit Borealin. This switch is essential for abscission checkpoint exit. Preventing the phosphorylation of Borealin leads to abscission failure, as does expression of a non-phosphorylatable Aurora B S227A mutant. Further, depletion of the ESCRT-III component and Aurora B substrate CHMP4C enables abscission, bypassing the PKCɛ–Aurora B exit pathway. Thus, we demonstrate that PKCɛ signals through Aurora B to exit the abscission checkpoint and complete cell ision.
PKCϵ Controls Mitotic Progression by Regulating Centrosome Migration and Mitotic Spindle Assembly
Publisher: American Association for Cancer Research (AACR)
Date: 2018
DOI: 10.1158/1541-7786.MCR-17-0244
Abstract: To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKCϵ) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase–anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCϵ in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKCϵ controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCϵ dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a characteristic of many transformed cells. Thus, PKCϵ appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCϵ as a potential cancer therapeutic target. Implications: The close relationship between PKCϵ dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G2 checkpoint, a hallmark of transformed cells, strongly suggests PKCϵ as a therapeutic target in cancer. Mol Cancer Res 16(1) 3–15. ©2017 AACR.
Supplementary Material from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425403
Abstract: One supplemental movie, four supplemental tables, six supplemental figures, supplemental methods
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431198.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Movie 1 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425400
Abstract: Movie of MT assembly rate assay
A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest
Publisher: Oxford University Press (OUP)
Date: 24-12-2018
DOI: 10.1093/NAR/GKY1295
Supplementary Material from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425403.V1
Abstract: One supplemental movie, four supplemental tables, six supplemental figures, supplemental methods
A cancer-associated, genome protective programme engaging PKCε
Publisher: Elsevier BV
Date: 12-2020
Supplementary Movie 1 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425400.V1
Abstract: Movie of MT assembly rate assay
Supplementary Table S3 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425391.V1
Abstract: RNA sequencing of HGSC cell lines
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431201
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431195.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Truncated MEK1 is required for transient activation of MAPK signalling in G2 phase cells
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.CELLSIG.2013.03.014
Abstract: The primary endpoint of signalling through the canonical Raf-MEK-ERK MAP kinase cascade is ERK activation. Here we report a novel signalling outcome for this pathway. Activation of the MAP kinase pathway by growth factors or phorbol esters during G2 phase results in only transient activations of ERK and p90RSK, then suppression to below control levels. A small peak of ERK and p90RSK activation in early G2 phase cells was identified, and inhibition of this delayed entry into mitosis. The previously identified, proteolytically cleaved form of MEK1 termed tMEK (truncated MEK1), is also induced with G2 phase MAPK pathway activation. We demonstrate that addition of recombinant mutants of MEK1 with an N-terminal truncation similar to that of tMEK also inhibited ERK and p90RSK activations and delayed progression into mitosis. Only catalytically inactive forms of tMEK were capable of these effects, but surprisingly, phosphorylation on the activating Ser218/222 sites was also required. A lack of MEK1 or ability to accumulate tMEK resulted in the absence of the feedback inhibition of ERK and p90RSK activations. tMEK is a novel output from the canonical MAP kinase signalling pathway, acting in a MAPK signalling-regulated dominant negative manner to inhibit ERK and p90RSK activations, acting as a d ening mechanism to reduce the magnitude or duration of MAPK pathway signalling in G2/M phase.
The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition
Publisher: Springer Science and Business Media LLC
Date: 13-03-2020
DOI: 10.1038/S41467-020-15163-6
Abstract: The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKCε phosphorylation of Aurora B S227. Assessing if this PKCε-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKCε also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKCε in by-passing the delay and resolution at anaphase entry that is associated with non-disjunction and catenation of sister chromatids. Implementation of this anaphase delay is reflected in PKCε activation following cell cycle dependent cleavage by caspase 7 knock-down of caspase 7 phenocopies PKCε loss, in a manner rescued by ectopically expressing/generating a free PKCε catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoIIα phosphorylation, a response necessary for catenation resolution during mitosis.
Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition
Publisher: Springer Science and Business Media LLC
Date: 03-06-2020
DOI: 10.1038/S41467-020-16468-2
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Mitotic catenation is monitored and resolved by a PKCε-regulated pathway
Publisher: Springer Science and Business Media LLC
Date: 08-12-2014
DOI: 10.1038/NCOMMS6685
Abstract: Exit from mitosis is controlled by silencing of the spindle assembly checkpoint (SAC). It is important that preceding exit, all sister chromatid pairs are correctly bioriented, and that residual catenation is resolved, permitting complete sister chromatid separation in the ensuing anaphase. Here we determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the SAC only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores. In addition, we show that this pathway is necessary to facilitate resolution of retained catenanes in mitosis. When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH-positive strands and chromosome bridging. These findings demonstrate the importance of PKCε-mediated regulation in protection from loss of chromosome integrity in cells failing to resolve catenation in G2.
Supplementary Table S2 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425397
Abstract: Genetic mutations in HGSC cell lines
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431186.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Table S3 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425391
Abstract: RNA sequencing of HGSC cell lines
Supplementary Table S4 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425388.V1
Abstract: RNA seq pathway analysis
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431198
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431189.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431192.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431192
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface
Publisher: eLife Sciences Publications, Ltd
Date: 05-2018
DOI: 10.7554/ELIFE.32271
Abstract: While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance.
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431195
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
MAPK pathway activation delays G2 /M progression by destabilizing Cdc25B
Publisher: Elsevier BV
Date: 12-2009
Supplementary Table S4 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2025
DOI: 10.1158/0008-5472.22425388
Abstract: RNA seq pathway analysis
Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention
Publisher: Portland Press Ltd.
Date: 18-06-2021
DOI: 10.1042/BCJ20210283
Abstract: A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues ision failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.
High prevalence of sessile serrated adenomas with BRAF mutations: A prospective study of patients undergoing colonoscopy
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1053/J.GASTRO.2006.08.038
Abstract: Sporadic colorectal cancers with a high degree of microsatellite instability are a clinically distinct subgroup with a high incidence of BRAF mutation and are widely considered to develop from serrated polyps. Previous studies of serrated polyps have been highly selected and largely retrospective. This prospective study examined the prevalence of sessile serrated adenomas and determined the incidence of BRAF and K-ras mutations in different types of polyps. An unselected consecutive series of 190 patients underwent magnifying chromoendoscopy. Polyp location, size, and histologic classification were recorded. All polyps were screened for BRAF V600E and K-ras codon 12 and 13 mutations. Polyps were detected in 72% of patients. Most (60%) were adenomas (tubular adenomas, tubulovillous adenomas), followed by hyperplastic polyps (29%), sessile serrated adenomas (SSAs 9%), traditional serrated adenomas (0.7%), and mixed polyps (1.7%). Adenomas were more prevalent in the proximal colon (73%), as were SSAs (75%), which tended to be large (64% >5 mm). The presence of at least one SSA was associated with increased polyp burden (5.0 vs 2.5 P < .0001) and female sex (P < .05). BRAF mutation was rare in adenomas (1/248 [0.4%]) but common in SSAs (78%), traditional serrated adenomas (66%), mixed polyps (57%), and microvesicular hyperplastic polyps (70%). K-ras mutations were significantly associated with goblet cell hyperplastic polyps and tubulovillous adenomas (P < .001). The prevalence of SSAs is approximately 9% in patients undergoing colonoscopy. They are associated with BRAF mutation, proximal location, female sex, and presence of multiple polyps. These findings emphasize the importance of identifying and removing these lesions for endoscopic prevention of colorectal cancer.
Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431183.V1
Abstract: Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Author response: Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface
Publisher: eLife Sciences Publications, Ltd
Date: 13-03-2018
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431186
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431201.V1
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Data from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513834
Abstract: Abstract Topoisomerase 2a (Topo2a)-dependent G sub /sub arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G sub /sub arrest by determining that p53–p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G sub /sub arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G sub /sub arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G sub /sub arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention. Significance: The identification of a requirement for p53 in stringent Topo2a-dependent G sub /sub arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality. /
Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431189
Abstract: Supplementary Figure from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/0008-5472.CAN-21-1785
Abstract: The identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality.
Tracking genome evolution in single cell clones reveals the rates and features of copy number alterations generated by ongoing chromosomal instability in cancer
Publisher: Cold Spring Harbor Laboratory
Date: 29-09-2023
Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431180
Abstract: Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 13-11-2020
DOI: 10.1158/0008-5472.CAN-19-0852
Abstract: These findings characterize multiple deregulated mechanisms of genome stability that lead to CIN in ovarian cancer and demonstrate the benefit of integrating analysis of said mechanisms into predictions of therapy response.
Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G<sub>2</sub> Arrest Requires p53 in hTERT-Positive Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431183
Abstract: Supplementary Table from Genome-Protective Topoisomerase 2a-Dependent G sub /sub Arrest Requires p53 in hTERT-Positive Cancer Cells
Supplementary Table S2 from Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22425397.V1
Abstract: Genetic mutations in HGSC cell lines
Related Organisations
The Francis Crick Institute
Location: United Kingdom of Great Britain and Northern Ireland
Barts Cancer Institute
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Tanya Soliman.