Functional role of Erg in prostate cancer

Erg 在前列腺癌中的功能作用

基本信息

批准号：
7919390
负责人：
Moshood Olatinwo
金额：
$ 12.43万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7919390
关键词：
AML1-ETO fusion protein Affect African American Agreement Alabama Androgens Apoptosis Apoptotic Automobile Driving Binding Breast Breast Cancer Cell CREB-binding protein CREB1 gene Cancer Center Cancer Research Project Cells Chimeric Proteins Code Collaborations Dominant-Negative Mutation Down-Regulation EP300 gene ETV1 gene Event Ewings sarcoma FUS-1 Protein Faculty Figs - dietary Fli-1 protein Future Gene Expression Gene Proteins Gene Targeting Genes Goals Human Image In Vitro Knock-out Laboratories Lead Length Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Mentors Minority Molecular Mus Myeloid Leukemia Nuclear Hormone Receptors Nuclear Receptors Pathway interactions Pilot Projects Play Property Prostate Prostatic Epithelium Prostatic Intraepithelial Neoplasias Protease Gene Protein p53 Proteins RNA-Binding Protein EWS RXR Regulation Research Retinoids Role Schools Serine Protease Signal Transduction Pathway Solid Neoplasm TMPRSS2 gene TP53 gene Testing Therapeutic Therapeutic Intervention Time Training Transactivation Transcription Coactivator Transcription Factor AP-1 Transcriptional Activation Transcriptional Regulation United States Viral Viral Oncogene Proteins Work alitretinoin cancer cell cancer health disparity career development cell immortalization cell transformation cellular retinoic acid binding protein II experience health disparity human CREBBP protein in vivo insight leukemia male men mutant programs protein function protein protein interaction research study restoration tumorigenesis

项目摘要

Reddy and his colleagues have identified, cloned and characterized human erg (ets related gene) gene and shown that it codes for sequence specific transcriptional activators. Erg gene is involved in the Ewing family of tumors and human myeloid leukemias. Erg and aberrant erg proteins were shown to inhibit apoptosis suggesting that this anti-apoptotic function may play a role in transformation. Erg gene is also shown to be fused with the prostate specific androgen regulated gene, TMPRSS2 in a majority of human prostate cancers resulting in the over expression of erg. African-American men in the United States are affected by prostate cancer in a disproportionate number compared to White men. Therefore, studying the role of erg in Drostate cancer becomes important for developing future therapeutic strategies and in reducing health disparity seen among African-American males. It was observed that erg related protein, Fli-1 and EWS-Fli-1 target CBP like E1A onco-protein resulting in transformation. Thus, viral transforming proteins and fusion onco-proteins appear to follow a similar strategy for transformation of cells. Interestingly, we have observed erg proteins to bind CBP suggesting that they may target transcriptional co-activators (CBP/p300) in prostate cancer cells resulting in the deregulation of multiple signal transduction pathways including regulation of apoptosis. These observations suggest that over expressed erg proteins target CBP resulting in survival of prostate cancer cells leading to transformation. Therefore, we have hypothesized that high levels of erg may be competing for CBP resulting in inhibition of CBP-mediated transcriptional activation properties of Retinoid X receptors (RXR alpha). Since transcriptional activation properties of RXR alpha are essential for apoptosis, it is reasonable to hypothesize that erg may interfere with RXR alpha/CBP-mediated apoptosis. This hypothesis will be tested both in vitro and in vivo. These studies will not only explain the molecular mechanism of activation of erg gene in human prostate cancers but also provide clues for therapeutic intervention.

雷迪（Reddy）和他的同事已经鉴定，克隆和特征的人ERG（ETS相关基因）基因和表明它代码为序列特定的转录激活剂。 ERG基因参与Ewing家族肿瘤和人类髓样白血病。 ERG和异常ERG蛋白显示可抑制凋亡表明这种抗凋亡功能可能在转化中起作用。 ERG基因也被证明是大多数人前列腺中与前列腺特异性雄激素调节基因融合的TMPRSS2 癌症导致ERG的过度表达。美国的非裔美国人受到与白人相比，前列腺癌的数量不成比例。因此，研究ERG在垂体癌对于制定未来的治疗策略和降低健康变得很重要非裔美国人男性之间存在差异。观察到ERG相关的蛋白质，FLI-1和EWS-FLI-1 靶标CBP如E1A Onco蛋白，导致转化。因此，病毒转化蛋白质和融合 Onco蛋白似乎遵循类似的细胞转化策略。有趣的是，我们观察到 ERG蛋白结合CBP，表明它们可以靶向前列腺中的转录共激活因子（CBP/P300）癌细胞导致了多个信号转导途径的管制，包括调节凋亡。这些观察结果表明，过度表达的ERG蛋白靶向CBP，导致生存前列腺癌细胞导致转化。因此，我们假设高水平的ERG可能竞争CBP，导致抑制类维生素类似CBP介导的转录激活特性 X受体（RXR alpha）。由于RXRα的转录激活特性对于凋亡至关重要，因此合理地假设ERG可能会干扰RXRα/CBP介导的凋亡。这假设将在体外和体内进行检验。这些研究不仅可以解释分子人类前列腺癌中ERG基因激活的机制，但也提供了治疗的线索干涉。