ORCID Profile
0000-0003-2213-1717
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Publisher: Portland Press Ltd.
Date: 07-2002
DOI: 10.1042/BJ20011751
Abstract: Sheep metallothionein-III (MT-III) cDNA was isolated from a brain cDNA library and characterized. In contrast with MT-III from other species, sheep MT-III cDNA is predicted to encode a protein with significantly different metal-binding properties, owing to the loss of three of its cysteine residues. RT-PCR from other sheep confirmed that this aberrant structure is ubiquitous in this species. MT-III was successfully isolated from sheep brain, demonstrating that the cDNA does give rise to a protein product of the predicted structure. Sheep MT-III is similar to other mammalian MT-IIIs in that it retains the Cys-Pro-Cys-Pro motif which is thought to encode growth-inhibitory activity, and we show that it is likewise able to inhibit neuron survival in vitro. This is the first naturally occurring variant of MT-III (or any other major mammalian MT gene) which gives rise to a protein product. These findings are discussed in light of proposed roles of MT in the mammalian brain.
Publisher: Wiley
Date: 23-11-2015
DOI: 10.1002/JCP.25119
Abstract: Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia.
Publisher: Wiley
Date: 07-02-2015
DOI: 10.1002/PROS.22954
Abstract: Integrin alpha2 beta1 (α2 β1 ) plays an integral role in tumour cell invasion, metastasis and angiogenesis, and altered expression of the receptor has been linked to tumour prognosis in several solid tumours. However, the relationship is complex, with both increased and decreased expression associated with different stages of tumour metastases in several tumour types. The ITGA2 gene, which codes for the α2 subunit, was examined to investigate whether a large CpG island associated with its promoter region is involved in the differential expression of ITGA2 observed in prostate cancer. Bisulphite sequencing of the ITGA2 promoter was used to assess methylation in formalin-fixed paraffin-embedded (FFPE) prostate tumour specimens and prostate cancer cell lines, PC3, 22Rv1 and LNCaP. Changes in ITGA2 mRNA expression were measured using quantitative PCR. ITGA2 functionality was interrogated using cell migration scratch assays and siRNA knockdown experiments. Bisulphite sequencing revealed strikingly decreased methylation at key CpG sites within the promoter of tumour s les, when compared with normal prostate tissue. Altered methylation of this CpG island is also associated with differences in expression in the non-invasive LNCaP, and the highly metastatic PC3 and 22Rv1 prostate cancer cell lines. Further bisulphite sequencing confirmed that selected CpGs were highly methylated in LNCaP cells, whilst only low levels of methylation were observed in PC3 and 22Rv1 cells, correlating with ITGA2 transcript levels. Examination of the increased expression of ITGA2 was shown to influence migratory potential via scratch assay in PC3, 22Rv1 and LNCaP cells, and was confirmed by siRNA knockdown experiments. Taken together, our data supports the assertion that epigenetic modification of the ITGA2 promoter is a mechanism by which ITGA2 expression is regulated.
Publisher: Rockefeller University Press
Date: 10-02-2003
DOI: 10.1084/JEM.20021039
Abstract: Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-κB activation. To investigate the relationship between NF-κB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-κB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between −174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-κB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-κB–dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-κB proteins binding to the CD28 response region of the promoter.
Publisher: Informa UK Limited
Date: 17-06-2019
Publisher: Wiley
Date: 13-06-2013
DOI: 10.1111/IMM.12100
Publisher: Oxford University Press (OUP)
Date: 07-01-2005
DOI: 10.1093/NAR/GKI161
Publisher: Public Library of Science (PLoS)
Date: 30-07-2012
Publisher: Wiley
Date: 14-11-2017
DOI: 10.1002/JCP.26197
Abstract: Integrins are transmembrane adhesion receptors that play an important role in hematopoiesis by facilitating interactions between hematopoietic cells and extracellular matrix components of the bone marrow and hematopoietic tissues. These interactions are important in regulating the function, proliferation, and differentiation of hematopoietic cells, as well as their homing and mobilization in the bone marrow. Not surprisingly altered expression and function of integrins plays a key role in the development and progression of cancer including leukemias. However, the regulation of integrin gene expression is not well characterized and the mechanisms by which integrin genes are disrupted in cancer remain unclear. Here we demonstrate for the first time that a key regulator of hematopoiesis, RUNX1, binds to and regulates the promoters of both the ITGA6 and ITGB4 genes in myeloid cells. The ITGA6 and ITGB4 integrin genes form the α6β4 integrin receptor. However, our data indicate that RUNX1 functions differently at these two promoters. RUNX1 regulates ITGA6 through a consensus RUNX1 binding motif in its promoter. In contrast, although the ITGB4 promoter is also activated by RUNX1, it does so in the absence of a recognized consensus RUNX1 binding motif. Furthermore, our data suggest that regulation of ITGB4 may involve interactions between the promoter and upstream regulatory elements.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S0161-5890(01)00094-3
Abstract: The controlled expression of cytokine genes is an essential component of an immune response. The specific types of cytokines as well as the time and place of their production is important in generating an appropriate immune response to an infectious agent. Aberrant expression is associated with pathological conditions of the immune system such as autoimmunity, atopy and chronic inflammation. Cytokine gene transcription is generally induced in a cell-specific manner. Over the last 15 years, a large amount of information has been generated describing the transcriptional controls that are exerted on cytokine genes. Recently, efforts have been directed at understanding how these genes are transcribed in a chromatin context. This review will discuss the mechanisms by which cytokine genes become available for transcription in a cell-restricted manner as well as the mechanisms by which these genes sense their environment and activate high level transcription in a transient manner. Particular attention will be paid to the role of chromatin in allowing transcription factor access to appropriate genes.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
DOI: 10.1007/S10549-021-06496-X
Abstract: ITGA2 encodes the integrin, α2 which mediates metastatic progression, and is a predictor of poor prognosis and chemoresistance in breast cancer. Decreased ITGA2 promoter methylation is implicated as a driver of increased gene expression in aggressive prostate and pancreatic tumours, however the contribution of altered methylation to ITGA2 expression changes in breast tumours has not been examined. ITGA2 gene methylation and gene expression was examined in publicly available breast cancer datasets, and ITGA2 promoter methylation was mapped by targeted bisulphite sequencing analysis in breast tumour cell lines. The expression of a putative regulatory long noncoding RNA (lncRNA) was examined by qPCR and its' functionality was investigated using gene knockdown (antisense oligonucleotides) and over expression in breast cancer cell lines. In breast tumours and breast cancer cell lines the ITGA2 promoter is largely unmethylated, with gene expression variable in tumour subtypes, irrespective of promoter methylation. A novel lncRNA (AC025180.1 ENSG00000249899), named herein I2ALR, was identified at the ITGA2 gene locus, and was variably expressed in breast tumours and breast cancer cell subtypes. I2LAR knockdown resulted in upregulation of ITGA2 gene expression, whilst over-expression of I2ALR resulted in downregulation of ITGA2 mRNA. Further, examination of two downstream targets of ITGA2 associated with breast tumor stemness and metastasis (CCND1 and ACLY), revealed concomitant gene expression changes in response to I2ALR modulation. I2ALR represents a novel regulatory molecule targeting ITGA2 expression in breast tumours a finding of significant and topical interest to the development of therapeutics targeting this integrin.
Publisher: Springer Science and Business Media LLC
Date: 2015
Publisher: Frontiers Media SA
Date: 29-09-2015
Publisher: Elsevier BV
Date: 09-2010
Publisher: Wiley
Date: 19-11-2016
DOI: 10.1002/JCB.25246
Abstract: Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia. RUNX1 regulates hematopoiesis through its control of genes important for hematopoietic cell growth, proliferation, and differentiation, including a number of cytokines and cytokine receptors. LIFR is regulated by two alternate promoters: a placental-specific and a ubiquitously active general promoter. We show that both of these promoters are regulated by RUNX1. However, in myeloid cells LIFR expression is driven solely by the general LIFR promoter with our data indicating that the placental promoter is epigenetically silenced in these cells. While RUNX1 activates the LIFR general promoter, the oncogenic RUNX1-ETO fusion protein generated by the t(8 ) translocation commonly associated with acute myeloid leukemia represses promoter activity. The data presented here establish LIFR as a transcriptional target of RUNX1 and suggest that disruption of RUNX1 activity in myeloid cells may result in altered LIFR signaling in these cells.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
DOI: 10.1007/S13402-022-00752-Y
Abstract: Integrins are integral to cell signalling and management of the extracellular matrix, and exquisite regulation of their expression is essential for a variety of cell signalling pathways, whilst disordered regulation is a key driver of tumour progression and metastasis. Most recently non-coding RNAs in the form of micro-RNA (miRNA) and long non-coding RNA (lncRNA) have emerged as a key mechanism by which tissue dependent gene expression is controlled. Whilst historically these molecules have been poorly understood, advances in ‘omic’ technologies and a greater understanding of non-coding regions of the genome have revealed that non-coding RNAs make up a large proportion of the transcriptome. This review examines the regulation of integrin genes by ncRNAs, provides and overview of their mechanism of action and highlights how exploitation of these discoveries is informing the development of novel chemotherapeutic agents in the treatment of cancer. MiRNA molecules have been the most extensively characterised and negatively regulate most integrin genes, classically regulating genes through binding to recognition sequences in the mRNA 3′-untranslated regions of gene transcripts. LncRNA mechanisms of action are now being elucidated and appear to be more varied and complex, and may counter miRNA molecules, directly engage integrin mRNA transcripts, and guide or block both transcription factors and epigenetic machinery at integrin promoters or at other points in integrin regulation. Integrins as therapeutic targets are of enormous interest given their roles as oncogenes in a variety of tumours, and emerging therapeutics mimicking ncRNA mechanisms of action are already being trialled.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2010
DOI: 10.2174/092986710790936329
Abstract: Changes to the epigenetic information within a cell play a significant role in cancer development and progression. These epigenetic changes are important in establishing the aberrant gene expression patterns that are a feature of cancer cell biology. We are currently experiencing a rapid advance in our understanding of how epigenetic information is written and interpreted in the cell, and the enzymes involved in these processes have been recognised as prime targets for therapeutic intervention. Reagents that target these enzymes have the potential to inhibit or reverse epigenetic changes in cancer cells. Evidence suggests that the aberrant regulation of two gene silencing pathways involving DNA methylation and histone methylation, play an important role in cancer development. Considerable effort is being exerted in the development of inhibitors of these pathways. However, complex functional interactions exist between the DNA and histone methylation pathways, and these interactions will need to be considered in the design of inhibitory molecules. This review details current research into agents developed as inhibitors of these epigenetic pathways, focusing on the types of epigenetic modifications being targeted, interactions between these modifications and the use of these inhibitory agents in cancer treatment.
Publisher: Impact Journals, LLC
Date: 14-06-2016
Publisher: Bentham Science Publishers Ltd.
Date: 10-2007
DOI: 10.2174/092986707782023271
Abstract: The chromatin structure of a gene plays an important role in regulating its expression. This structure is established through the action of various protein complexes that remodel nucleosomes, catalyse post-translational modifications, deposit histone variants and methylate DNA. Together these complexes establish epigenetic marks that influence expression of the gene. Some of these epigenetic marks are transient while others, such as those involved in silencing genes are more stable and can require several cell isions to be fully implemented or reversed. Deregulated gene expression programs are a feature of cancer biology and it is now apparent that epigenetic changes, as well as genetic changes, are important in establishing these aberrant expression patterns. However, unlike genetic alterations, epigenetic changes are reversible. The complexes that catalyse these modifications therefore represent valuable targets for therapeutic intervention. Here we will review the most recent literature describing the protein complexes that catalyse epigenetic modifications and the inhibitors of these complexes that are being pursued as cancer drugs. In addition we will highlight those epigenetic modifiers that provide promise as therapeutic targets but for which inhibitors are not currently available.
Publisher: Bentham Science Publishers Ltd.
Date: 08-2006
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: SAGE Publications
Date: 02-2014
Abstract: It is now well established that both genetic and environmental factors contribute to and interact in the development of multiple sclerosis (MS). However, the currently described causal genetic variants do not explain the majority of the heritability of MS, resulting in ‘missing heritability’. Epigenetic mechanisms, which principally include DNA methylation, histone modifications and microRNA-mediated post-transcriptional gene silencing, may contribute a significant component of this missing heritability. As the development of MS is a dynamic process potentially starting with inflammation, then demyelination, remyelination and neurodegeneration, we have reviewed the dynamic epigenetic changes in these aspects of MS pathogenesis and describe how environmental risk factors may interact with epigenetic changes to manifest in disease.
Publisher: Oxford University Press (OUP)
Date: 29-02-2008
DOI: 10.1093/NAR/GKN117
Publisher: InTech
Date: 25-11-2011
DOI: 10.5772/1285
Publisher: Springer Science and Business Media LLC
Date: 14-06-2011
DOI: 10.1007/S13148-011-0041-7
Abstract: Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2016
Publisher: MDPI AG
Date: 14-04-2015
DOI: 10.3390/MD13042327
Publisher: Informa UK Limited
Date: 2004
No related organisations have been discovered for Adele Holloway.
Start Date: 2005
End Date: 2005
Funder: National Health & Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2007
End Date: 2007
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2007
End Date: 2007
Funder: David Collins Leukaemia Foundation
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2004
End Date: 2004
Funder: National Health & Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2009
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2010
End Date: 2010
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2011
End Date: 2011
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Cancer Council of Tasmania
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