ORCID Profile
0000-0002-4304-4586
Current Organisation
University of Tasmania
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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: Informa UK Limited
Date: 17-05-2023
Publisher: Public Library of Science (PLoS)
Date: 30-01-2009
Publisher: Informa UK Limited
Date: 17-06-2019
Publisher: Bentham Science Publishers Ltd.
Date: 08-2006
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2007
DOI: 10.1101/GR.6022807
Abstract: The centromere is a complex structure, the components and assembly pathway of which remain inadequately defined. Here, we demonstrate that centromeric α-satellite RNA and proteins CENPC1 and INCENP accumulate in the human interphase nucleolus in an RNA polymerase I–dependent manner. The nucleolar targeting of CENPC1 and INCENP requires α-satellite RNA, as evident from the delocalization of both proteins from the nucleolus in RNase-treated cells, and the nucleolar relocalization of these proteins following α-satellite RNA replenishment in these cells. Using protein truncation and in vitro mutagenesis, we have identified the nucleolar localization sequences on CENPC1 and INCENP. We present evidence that CENPC1 is an RNA-associating protein that binds α-satellite RNA by an in vitro binding assay. Using chromatin immunoprecipitation, RNase treatment, and “RNA replenishment” experiments, we show that α-satellite RNA is a key component in the assembly of CENPC1, INCENP, and survivin (an INCENP-interacting protein) at the metaphase centromere. Our data suggest that centromere satellite RNA directly facilitates the accumulation and assembly of centromere-specific nucleoprotein components at the nucleolus and mitotic centromere, and that the sequestration of these components in the interphase nucleolus provides a regulatory mechanism for their timely release into the nucleoplasm for kinetochore assembly at the onset of mitosis.
Publisher: Oxford University Press (OUP)
Date: 07-01-2005
DOI: 10.1093/NAR/GKI161
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: 11-2011
Publisher: Public Library of Science (PLoS)
Date: 30-07-2012
Publisher: Oxford University Press (OUP)
Date: 29-02-2008
DOI: 10.1093/NAR/GKN117
Publisher: American Association for Cancer Research (AACR)
Date: 05-2011
DOI: 10.1158/1078-0432.CCR-10-2915
Abstract: Purpose: Patients presenting with locally advanced rectal cancer currently receive preoperative radiotherapy with or without chemotherapy. Although pathologic complete response is achieved for approximately 10% to 30% of patients, a proportion of patients derive no benefit from this therapy while being exposed to toxic side effects of treatment. Therefore, there is a strong need to identify patients who are unlikely to benefit from neoadjuvant therapy to help direct them toward alternate and ultimately more successful treatment options. Experimental Design: In this study, we obtained expression profiles from pretreatment biopsies for 51 rectal cancer patients. All patients underwent preoperative chemoradiotherapy, followed by resection of the tumor 6 to 8 weeks posttreatment. Gene expression and response to treatment were correlated, and a supervised learning algorithm was used to generate an original predictive classifier and validate previously published classifiers. Results: Novel predictive classifiers based on Mandard's tumor regression grade, metabolic response, TNM (tumor node metastasis) downstaging, and normal tissue expression profiles were generated. Because there were only 7 patients who had minimal treatment response (& % residual tumor), expression profiles were used to predict good tumor response and outcome. These classifiers peaked at 82% sensitivity and 89% specificity however, classifiers with the highest sensitivity had poor specificity, and vice versa. Validation of predictive classifiers from previously published reports was attempted using this cohort however, sensitivity and specificity ranged from 21% to 70%. Conclusions: These results show that the clinical utility of microarrays in predictive medicine is not yet within reach for rectal cancer and alternatives to microarrays should be considered for predictive studies in rectal adenocarcinoma. Clin Cancer Res 17(9) 3039–47. ©2011 AACR.
Publisher: Frontiers Media SA
Date: 29-09-2015
Publisher: Wiley
Date: 28-06-2013
DOI: 10.1002/JSO.23357
Abstract: The phosphatidylinositide 3-kinase (PI3K) pathway is an important signalling pathway that is frequently activated in cancer cells. This has led to the emergence of PI3K inhibitors as potential new treatment modalities for many cancers. We have investigated the frequency of molecular changes in the PI3K pathway in gastric cancer. A series of sixty one human gastric cancer specimens and nine human gastric cancer cell lines were screened for PIK3CA mutations and copy number gain by direct sequencing and multiplex ligation-dependent probe lification (MLPA), respectively. PTEN protein levels were assessed by immunohistochemistry. Alterations in the PI3K pathway were found in 33 of 61 (54%) gastric tumours. PIK3CA mutation and copy number gain were detected in 3 (4.9%) and 8 (13.1%), respectively, of 61 gastric cancer s les while PTEN loss was detected in 24 (39%) of the tumours. Two tumours had both PTEN loss and PIK3CA copy number gain. There were no significant associations between these PI3K pathway changes and the clinical features of the tumours. Alterations in the PI3K pathway are frequent in gastric tumours implicating this pathway as a legitimate therapeutic target in gastric cancer.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2011
DOI: 10.1245/S10434-010-1433-1
Abstract: Cancer treatment is now moving toward a personalized approach, promising improved rates of response and survival. A number of studies have employed the use of microarrays to investigate the predictive potential of expression profiling in gastrointestinal (GI) cancer patients. However while many robust predictive classifiers relating to response and prognosis have been generated for GI cancer patients, these have yet to make the transition to the clinic. The main obstacle is the limited cross validation between predictive gene lists identified for the same tumor type and outcome. Differences in the experimental design, analysis, and interpretation of results all contribute to this variation, with numerous factors influencing which genes are highlighted as predictive. While predictive genomics shows immense potential, it is still a relatively new field and the validation of predictive gene lists derived from microarray data remains a challenge. Future studies must carefully consider all aspects of experimental design to ensure a clinically applicable predictive test can be developed. With this in mind, more extensive and collaborative research must be undertaken before microarray-based platforms can be used routinely in tailoring GI cancer treatment and change clinical practice. Larger cohorts and consistency in methodology will enable the findings from this research to make the transition to the clinic.
No related grants have been discovered for Kate Brettingham-Moore.