ORCID Profile
0000-0002-3155-0334
Current Organisations
Queensland University of Technology
,
University of Limerick
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Publisher: Springer Science and Business Media LLC
Date: 10-05-2019
Publisher: Frontiers Media SA
Date: 15-02-2022
Publisher: Wiley
Date: 12-2017
DOI: 10.1002/CPPH.31
Abstract: Acetylation is a core cellular process involved in maintaining genomic integrity, gene regulation, and metabolism. Histone acetyltransferases (HATs) are an enzyme family that regulates these processes by catalyzing the transfer of an acetyl moiety onto target proteins. Perturbations of cellular acetylation profiles have been associated with a variety of disease states, including cancer. Changes in acetylation profiles can be achieved by mechanisms associated with acetyltransferases, such as gene down-regulation or alterations in the activity of key acetyltransferase enzymes. An important set of tools for quantifying enzyme activity are in vitro histone acetylation assays, using either endogenous or tagged overexpressed proteins. Detailed in this unit is an in vitro acetylation assay used to quantify HAT activity. © 2017 by John Wiley & Sons, Inc.
Publisher: MDPI AG
Date: 07-07-2020
Abstract: Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308–0.943, p 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.
Publisher: No publisher found
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 19-07-2019
Publisher: Springer Science and Business Media LLC
Date: 04-04-2017
Publisher: Wiley
Date: 2012
Publisher: Frontiers Media SA
Date: 31-05-2019
Publisher: MDPI AG
Date: 07-10-2022
DOI: 10.3390/CURRONCOL29100591
Abstract: Breast cancer represents a heterogeneous condition in which the interaction between host immune response and primary oncogenic events can impact disease progression. Ratios of systemic blood-based immunocytes have emerged as clinically-relevant prognostic biomarkers in cancer patients. The NLR (neutrophil-to-lymphocyte ratio) has been shown to be prognostic in a variety of cancers, including breast cancer. However, evaluation of the prognostic value for overall survival (OS) and disease-free survival (DFS) of other key immunocyte ratios—neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-white cell count ratio (NWR), lymphocyte-to-white cell count ratio (LWR), monocyte-to-white cell count ratio (MWR), platelet-to-lymphocyte (PLR)—by breast cancer subtypes in a neoadjuvant chemotherapy (NAC) cohort remains to be fully explored. An NAC-treated breast cancer cohort, comprised of Luminal A, Luminal B, HER2-positive, and triple negative/basal breast cancers, treated at a tertiary referral center (minimum 3-year follow-up), was used to calculate immunocyte ratios and immunocyte cut-off values, calculated with % specificity (using decision tree modeling). The association with subtype-specific OS, DFS, and tumor grade was analyzed using cut offs calculated using both receiver operating characteristic curves and decision tree modelling. Decision tree calculated ratios showed that LMR (5.29) and MWR (0.06) were significantly associated with Luminal A OS (p = 0.004 and p = 0.022) and DFS (p = 0.004 and p = 0.022), and Luminal B OS (p = 0.027 and p = 0.008) and DFS (p = 0.005 and p = 0.007). NLR (1.79) and LWR (0.30) were significantly associated with HER2-positive OS (p = 0.013 and p = 0.043). NLR (1.79) and NWR (0.62) were significantly associated with DFS (p = 0.035 and p = 0.021). No significant association we observed between any immunocyte ratio in the triple negative cohort. Our results demonstrate the subtype-specific prognostic value of immunocyte ratios in NAC-treated breast cancer patients. Further validation of immunocyte ratios will provide clinicians with a new prognostic aid for disease management and monitoring.
Publisher: Frontiers Media SA
Date: 2022
Publisher: MDPI AG
Date: 25-10-2017
Publisher: MDPI AG
Date: 13-05-2018
Publisher: Oxford University Press (OUP)
Date: 19-12-2013
DOI: 10.1002/STEM.1222
Abstract: The regeneration of the hematopoietic system following total body irradiation is supported by host-derived mesenchymal stromal cells (MSCs) within the bone marrow. The mechanisms used by MSCs to survive radiation doses that are lethal to the hematopoietic system are poorly understood. The DNA damage response (DDR) represents a cohort of signaling pathways that enable cells to execute biological responses to genotoxic stress. Here, we examine the role of the DDR in mediating the resistance of MSCs to ionizing radiation (IR) treatment using two authentic clonal mouse MSC lines, MS5 and ST2, and primary bulk mouse MSCs. We show that multiple DDR mechanisms contribute to the radio-resistance of MSCs: robust DDR activation via rapid γ-H2AX formation, activation of effective S and G2/M DNA damage checkpoints, and efficient repair of IR-induced DNA double-strand breaks. We show that MSCs are intrinsically programmed to maximize survival following IR treatment by expressing high levels of key DDR proteins including ATM, Chk2, and DNA Ligase IV high levels of the anti-apoptotic, Bcl-2 and Bcl-XL and low levels of the pro-apoptotic, Bim and Puma. As a result, we demonstrate that irradiated mouse MSCs withstand IR-induced genotoxic stress, continue to proliferate, and retain their capacity to differentiate long-term along mesenchymal-derived lineages. We have shown, for the first time, that the DDR plays key roles in mediating the radioresistance of mouse MSCs which may have important implications for the study and application of MSCs in allogeneic bone marrow transplantation, graft-versus-host disease, and cancer treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2015
DOI: 10.1158/1538-7445.SABCS14-P4-07-05
Abstract: Introduction Cellular communication in the primary tumour micro-environment is known to play a key role in tumour development and progression. Exosomes are membrane-derived nanovesicles that are actively secreted by cells. Exosomes have been implicated in cell-to-cell communication through the transfer of genetic material including messenger RNA (mRNA), and more recently microRNA (miRNA). miRNAs are small non-coding RNAs approximately 22 nucleotides in length. They play an important role in posttranscriptional regulation of gene expression. Recent reports suggest exosome-mediated trafficking of microRNAs between cells. The aim of this study was to identify the panel of exosome-encapsulated microRNAs secreted by breast cancer cells in vitro. Methods Four breast cancer cell lines, MDA-MB-231, BT-20, Sk-Br-3 and T47D were cultured in exosome-depleted media for 48 hours. Exosomes secreted by the cells were isolated through a process of differential centrifugation, microfiltration and ultracentrifugation. The presence of exosomes was first confirmed by Transmission Electron Microscopy (TEM) and Western Blot analysis. Global miRNA array analysis of RNA extracted from exosomes was performed to identify the panel of miRNAs secreted by these cells. miRNA targets of interest were further validated using relative quantification PCR (RQ-PCR). Transfer of Red fluorescent protein (RFP)-labelled exosomes between cell populations was visualized using Confocal microscopy. Results TEM analysis of secreted exosomes revealed vesicular bodies of 40-100nm in size. Immunoblotting confirmed the presence of the exosome-associated protein CD63. MicroRNA array analysis of exosome fractions targeting 2089 miRNAs, revealed secretion of between 324 and 394 miRNAs by the cell lines. The miRNAs appeared to cluster in a biologically relevant fashion. 282 miRNAs were common to exosomes from all 4 cell lines, while a small selection were specific to in idual cell lines. Exosome-mediated trafficking of miRNA targets of interest including miR-451a and miR-744-5p was successfully validated using RQ-PCR. Further validated targets included miR-10b, miR-145, miR-492 and miR-498, all of which have established roles in regulation of proliferation and apoptosis in cancer. Confocal microscopy supported visualization of miRNA-enriched exosome release from donor cells and subsequent uptake of the RFP-labelled exosomes by recipient cells. Conclusions A distinct panel of miRNAs are actively and selectively packaged into exosomes and secreted by breast cancer cells. This transfer of functional miRNAs between cells may play an important role in intercellular communication in the primary tumour microenvironment. The data presented also has potentially important implications in the identification of a circulating miRNA signature for breast cancer detection. Citation Format: Doireann P Joyce, Claire L Glynn, James Brown, Emma Holian, Peter Dockery, Michael J Kerin, Roisin M Dwyer. Exosome-mediated trafficking of microRNAs by breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2015 (9 Suppl):Abstract nr P4-07-05.
Publisher: Informa UK Limited
Date: 11-2011
DOI: 10.1128/MCB.05987-11
Publisher: Frontiers Media SA
Date: 21-09-2021
DOI: 10.3389/FCELL.2021.720194
Abstract: The effects of genotoxic stress can be mediated by activation of the Ataxia Telangiectasia Mutated (ATM) kinase, under both DNA damage-dependent (including ionizing radiation), and independent (including hypoxic stress) conditions. ATM activation is complex, and primarily mediated by the lysine acetyltransferase Tip60. Epigenetic changes can regulate this Tip60-dependent activation of ATM, requiring the interaction of Tip60 with tri-methylated histone 3 lysine 9 (H3K9me3). Under hypoxic stress, the role of Tip60 in DNA damage-independent ATM activation is unknown. However, epigenetic changes dependent on the methyltransferase Suv39H1, which generates H3K9me3, have been implicated. Our results demonstrate severe hypoxic stress (0.1% oxygen) caused ATM auto-phosphorylation and activation (pS1981), H3K9me3, and elevated both Suv39H1 and Tip60 protein levels in FTC133 and HCT116 cell lines. Exploring the mechanism of ATM activation under these hypoxic conditions, siRNA-mediated Suv39H1 depletion prevented H3K9me3 induction, and Tip60 inhibition (by TH1834) blocked ATM auto-phosphorylation. While MDM2 (Mouse double minute 2) can target Suv39H1 for degradation, it can be blocked by sirtuin-1 (Sirt1). Under severe hypoxia MDM2 protein levels were unchanged, and Sirt1 levels depleted. SiRNA-mediated depletion of MDM2 revealed MDM2 dependent regulation of Suv39H1 protein stability under these conditions. We describe a novel molecular circuit regulating the heterochromatic state (H3K9me3 positive) under severe hypoxic conditions, showing that severe hypoxia-induced ATM activation maintains H3K9me3 levels by downregulating MDM2 and preventing MDM2-mediated degradation of Suv39H1. This novel mechanism is a potential anti-cancer therapeutic opportunity, which if exploited could target the hypoxic tumor cells known to drive both tumor progression and treatment resistance.
Publisher: Wiley
Date: 06-05-2016
DOI: 10.1002/BMB.20954
Abstract: A pedagogic intervention, in the form of an inquiry-based peer-assisted learning project (as a practical student-led bioinformatics module), was assessed for its ability to increase students' engagement, practical bioinformatic skills and process-specific knowledge. Elements assessed were process-specific knowledge following module completion, qualitative student-based module evaluation and the novelty, scientific validity and quality of written student reports. Bioinformatics is often the starting point for laboratory-based research projects, therefore high importance was placed on allowing students to in idually develop and apply processes and methods of scientific research. Students led a bioinformatic inquiry-based project (within a framework of inquiry), discovering, justifying and exploring in idually discovered research targets. Detailed assessable reports were produced, displaying data generated and the resources used. Mimicking research settings, undergraduates were ided into small collaborative groups, with distinctive central themes. The module was evaluated by assessing the quality and originality of the students' targets through reports, reflecting students' use and understanding of concepts and tools required to generate their data. Furthermore, evaluation of the bioinformatic module was assessed semi-quantitatively using pre- and post-module quizzes (a non-assessable activity, not contributing to their grade), which incorporated process- and content-specific questions (indicative of their use of the online tools). Qualitative assessment of the teaching intervention was performed using post-module surveys, exploring student satisfaction and other module specific elements. Overall, a positive experience was found, as was a post module increase in correct process-specific answers. In conclusion, an inquiry-based peer-assisted learning module increased students' engagement, practical bioinformatic skills and process-specific knowledge. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:304-313 2016.
Publisher: Springer New York
Date: 09-11-2016
DOI: 10.1007/978-1-4939-6524-3_18
Abstract: The purpose of this chapter is to provide a starting point for the analysis of miRNA array data, using freely available online suites of tools. This chapter does not describe how to perform analysis of primary array data, rather how to use the top differentially regulated miRNA (returned from comparing one miRNA group to another) as the starting point for further practical analysis.Here we describe the methods and tools required to identify targets worthy of additional investigation, using the identified miRNA as a starting point. Importantly, this additional information (pathways targeted, gene expression, mRNA targets, miRNA families) can be used to positively inform any project.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
Publisher: Springer Science and Business Media LLC
Date: 20-06-2014
DOI: 10.1038/SREP05372
Publisher: Frontiers Media SA
Date: 03-11-2021
DOI: 10.3389/FCELL.2021.747314
Abstract: Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 09-05-2022
DOI: 10.1101/2022.05.09.490051
Abstract: Centrosome lification (CA) is a prominent feature of human cancers linked to genomic instability and tumourigenesis in vivo . CA is observed as early as pre-malignant metaplasia, with CA incidence increasing as the disease progresses from dysplasia to neoplasia. However, the mechanistic contributions of CA to tumourigenesis (tumour architecture and remodelling) are poorly understood. Using non-tumourigenic breast cells (MCF10A), we demonstrate that CA induction (by CDK1 inhibition or PLK4 overexpression) alone increased both cell migration, invasion and Extracellular Matrix (ECM) remodeling. Mechanistically, CA induction activated small GTPase Rap-1. We demonstrated the key role of Rap-1 mediated signalling in CA induced tumourigenesis through Rap-1 inhibition (using GGTI-298) which blocked CA-induced migration, invasion and ECM attachment. CA induction in a long-term MCF10A cell culture system disrupted epithelial cell-cell junction integrity, via dysregulation of expression and subcellular localisation of cell junction proteins (ZO-1, Occludin, JAM-A & β-catenin). At the ultrastructural level, CA significantly inhibited apical junctional complex formation, as visualized by transmission electron microscopy. CA induction in the luminal A breast cancer cell line MCF7 revealed similar trends in cell junction disruption. Furthermore, CA induction in MCF10A elevated expression of integrin β-3, matrix metalloprotease MMP1 and MMP13 facilitating the observed ECM attachment, degradation and cell invasion phenotype. In vivo validation using a Chicken Embryo xenograft model, showed CA positive (CA+) MCF10A cells invaded into the chicken mesodermal layer, characterised by inflammatory cell infiltration and a marked focal reaction between chorioallantoic membrane and cell graft. This reaction was inhibited by pre-treatment of CA+ MCF10A cells with GGTI-298. Interestingly, in metastatic breast cancer cells with high levels of endogenous CA (triple negative cell line MDA-MB-231) inhibition of this CA-signalling pathway (using PLK4 inhibitor Centrinone B) abrogated their metastatic capacity in vitro . This demonstrates dual roles for CA signalling, for initiating and maintaining the CA-induced metastatic phenotype. Here, we demonstrated that CA induction in normal non-tumourigenic cells acts through Rap-1-dependent signaling to confer early pro-tumourigenic changes promoting tumour progression, mediated by ECM disruption, and altered cell-cell contacts. These insights reveal that in normal cells, CA induction alone (without additional pro-tumorigenic alterations) is sufficient to induce tumourigenesis and CA-mediated signaling supports a metastatic phenotype. Centrosome lification alone drives early tumourigenic change in normal breast epithelial cells
Publisher: Springer Science and Business Media LLC
Date: 19-10-2009
DOI: 10.1038/ONC.2009.340
Abstract: Abnormal centrosome numbers arise in tumours and can cause multipolar mitoses and genome instability. Cdk2 controls normal centrosome duplication, but Chk1-dependent centrosome lification also occurs after DNA damage. We investigated the involvement of cyclin-dependent kinases (Cdks) in DNA damage-induced centrosome lification using cells lacking either Cdk2, or both Cdk1 and Cdk2 activity. Cdk2(-/-) DT40 cells showed robust centrosome lification after ionizing radiation (IR), whereas Cdk1-deficient Cdk2(-/-) cells showed no centrosome lification, demonstrating that Cdk1 can substitute for Cdk2 in this pathway. Surprisingly, we found that Cdk2 activity was upregulated by IR in wild-type but not in Chk1(-/-) DT40 cells. Cdk2 upregulation also occurred in HeLa cells after IR treatment. Chk1-dependent Cdk2 induction was not accompanied by increased levels of Cdk1, Cdk2, cyclin A or cyclin E, but activating T160 phosphorylation of Cdk2 increased after IR. Moreover, Cdk2 overexpression restored IR-induced centrosome lification in Cdk1-deficient Cdk2(-/-) cells, but T160A mutation blocked this rescue. Our data suggest that Chk1 signalling causes centrosome lification after IR by upregulating Cdk2 activity through activating phosphorylation.
Publisher: Future Science Ltd
Date: 2020
Abstract: Lysine (or histone) acetyltransferases plays a key role in genome maintenance and gene regulation and dysregulation of acetylation is a recognized feature of many diseases, including several cancers. Here, the patent landscape surrounding lysine acetyltransferase inhibitors (KATi or HATi), with a focus on small-molecule compounds, is outlined and assessed. Overall, the 36 KATi-specific patents found were categorized into two distinct groups: specific small-molecule inhibitors (compounds and molecules) and patents applying KATi for targeted disease treatment. These patents recognize the emergent potential of KATi to significantly impact on the management of many diseases (including multiple cancer types, neurological disorders and immunological syndromes), improving the range of treatments (and drug classes) available for personalized medicine.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2015
DOI: 10.1186/S13287-015-0125-Y
Abstract: Bone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells, are the focus of intensive efforts worldwide to elucidate their function and biology. Despite the importance of BMSC migration for their potential therapeutic uses, the mechanisms and signalling governing stem cell migration are still not fully elucidated. We investigated and detailed the effects of MCP-1 activation on BMSCs by using inhibitors of G protein-coupled receptor alpha beta (GPCR αβ), ROCK (Rho-associated, coiled-coil containing protein kinase), and PI3 kinase (PI3K). The effects of MCP-1 stimulation on intracellular signalling cascades were characterised by using immunoblotting and immunofluorescence. The effectors of MCP-1-mediated migration were investigated by using migration assays (both two-dimensional and three-dimensional) in combination with inhibitors. We established the kinetics of the MCP-1-activated signalling cascade and show that this cascade correlates with cell surface re-localisation of chemokine (C motif) receptor 2 (CCR2) (the MCP-1 receptor) to the cell periphery following MCP-1 stimulation. We show that MCP-1-initiated signalling is dependent on the activation of βγ subunits from the GPCR αβγ complex. In addition, we characterise a novel role for PI3Kγ signalling for the activation of both PAK and ERK following MCP-1 stimulation. We present evidence that the Gβγ complex is responsible for PI3K/Akt, PAK, and ERK signalling induced by MCP-1 in BMSCs. Importantly, we found that, in BMSCs, inhibition of ROCK significantly inhibits MCP-1-induced chemotactic migration, in contrast to previous reports in other systems. Our results indicate differential chemotactic signalling in mouse BMSCs, which has important implications for the translation of in vivo mouse model findings into human trials. We identified novel components and interactions activated by MCP-1-mediated signalling, which are important for stem cell migration. This work has identified additional potential therapeutic targets that could be manipulated to improve BMSC delivery and homing.
Publisher: MDPI AG
Date: 08-01-2017
Publisher: Springer Science and Business Media LLC
Date: 03-2017
Publisher: Wiley
Date: 30-01-2016
DOI: 10.1002/IJC.29985
Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2016
DOI: 10.1158/0008-5472.CAN-16-0860
Abstract: Insights distilled from integrating multiple big-data or “omic” datasets have revealed functional hierarchies of molecular networks driving tumorigenesis and modifiers of treatment response. Identifying these novel key regulatory and dysregulated elements is now informing personalized medicine. Crucially, although there are many advantages to this approach, there are several key considerations to address. Here, we examine how this big data–led approach is impacting many erse areas of cancer research, through review of the key presentations given at the Irish Association for Cancer Research Meeting and importantly how the results may be applied to positively affect patient outcomes. Cancer Res 76(21) 6167–70. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
DOI: 10.1038/S41598-019-40221-5
Abstract: Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options redict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo , quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.SCR.2014.06.006
Abstract: Currently there is intense interest in using mesenchymal stem cells (MSC) for therapeutic interventions in many diseases and conditions. To accelerate the therapeutic use of stem cells we must understand how they sense their environment. Primary cilia are an extracellular sensory organelle present on most growth arrested cells that transduce information about the cellular environment into cells, triggering signaling cascades that have profound effects on development, cell cycle, proliferation, differentiation and migration. Migrating cells likely encounter differing oxygen tensions, therefore we investigated the effect of oxygen tension on cilia. Using bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) we found that oxygen tension significantly affected the length of cilia in primary BMSCs. Chronic exposure to hypoxia specifically down-regulated genes involved in hedgehog signaling and re-localized the Smo and Gli2 proteins to cilia. Investigating the effects of chemotactic migration on cilia, we observed significantly longer cilia in migrating cells which was again, strongly influenced by oxygen tension. Finally, using computational modeling we identified links between migration and ciliation signaling pathways, characterizing the novel role of HSP90 and PI3K signaling in regulating BMSC cilia length. These findings enhance our current understanding of BMSC adaptions to hypoxia and advance our knowledge of BMSC biology and cilia regulation.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-12-2013
Abstract: SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1 -deficient animals represent a model of inflammation-enhanced cancer development.
Publisher: Portland Press Ltd.
Date: 15-08-2016
DOI: 10.1042/BST20160081
Abstract: Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.
Publisher: Informa UK Limited
Date: 20-11-2020
Publisher: Frontiers Media SA
Date: 15-08-2022
Publisher: Public Library of Science (PLoS)
Date: 07-06-2023
DOI: 10.1371/JOURNAL.PONE.0286826
Abstract: The development and practice of good leadership skills (distinct from management skills) enhances both an in idual’s career development, and their organization. However, universities are known to present unique issues around the development, and practice, of good leadership. Good leadership skills should be considered essential for university staff who train (and mentor) staff or students. Currently, there is no clear evidence that staff in the biological (life) sciences undergo formal (routine) leadership skills training (or appraisal). Furthermore, what leadership training this group needs, or wants, is unknown. A questionnaire was designed to explore leadership dimensions (roles, training, perceptions, and attitudes), and incorporated the Leadership Attitudes and Belief scale (LABS) instrument. Including LABS allows evaluation of leadership attitudes as either Systemic (in idual responsibility) or Hierarchical (chain-of-command). Self-selecting biological science academics and staff were recruited using an online survey. Analysis focused on academic staff (lecturer/Assistant professor, and above), and explored the relationship of leadership dimensions with key categories (career stage, gender, age, role, and professional experience). Staff were found to be knowledgeable about what leadership is, but strongly desire formal training in leadership skills and practice. Importantly, staff did not have access to specific leadership training (but did have access to management training), but felt strongly that gaining leadership skills would improve their professional skill set. Analysis found that academics in the biological sciences were oriented towards Systemic leadership, a more collective and supportive approach. It was clear that while good leadership skills are highly valued by academic staff, in practice these skills are underprovided in the biological sciences workplace. This work provides a profile, and benchmark, of leadership (current skills, and desired needs) in the biological sciences. These results provide evidence for the need to embed specific leadership skills training into professional development (and teaching) programmes in the biological sciences.
Publisher: No publisher found
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 27-02-2015
Publisher: PeerJ
Date: 17-03-2015
DOI: 10.7717/PEERJ.829
Publisher: No publisher found
Date: 2014
Publisher: MDPI AG
Date: 22-05-2015
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1002/BJS.9822
Publisher: Springer Science and Business Media LLC
Date: 20-02-2018
Publisher: No publisher found
Date: 2014
Start Date: 2014
End Date: 2015
Funder: Enterprise Ireland
View Funded ActivityStart Date: 2016
End Date: 2026
Funder: Enterprise Ireland
View Funded ActivityStart Date: 2016
End Date: 2017
Funder: Enterprise Ireland
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: Wellcome Trust
View Funded Activity