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：
7425149
负责人：
Moshood Olatinwo
金额：
$ 15.17万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7425149
关键词：
AML1-ETO fusion protein Affect African American Agreement Androgens Apoptosis Apoptotic Automobile Driving Binding Breast Breast Cancer Cell CREB-binding protein CREB1 gene 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 Numbers Pathway interactions Personal Satisfaction Pilot Projects Play Program Development Property Prostate Prostatic Epithelium Prostatic Intraepithelial Neoplasias Protease Gene Protein p53 Proteins RNA-Binding Protein EWS RXR Regulation Research Retinoids Role 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 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.

Reddy 和他的同事已经鉴定、克隆并表征了人类 erg（ets 相关基因）基因，并显示它编码序列特异性转录激活剂。 Erg基因涉及尤因家族肿瘤和人类骨髓性白血病。 Erg 和异常 erg 蛋白被证明可以抑制细胞凋亡表明这种抗凋亡功能可能在转化中发挥作用。 Erg 基因也被证明在大多数人类前列腺中与前列腺特异性雄激素调节基因 TMPRSS2 融合癌症导致 erg 过度表达。美国的非洲裔男性受到以下因素的影响与白人相比，前列腺癌的数量不成比例。因此，研究 erg 在果状癌对于制定未来的治疗策略和减少健康变得重要非裔美国男性之间存在差异。观察到erg相关蛋白Fli-1和EWS-Fli-1 靶向 CBP，如 E1A 癌蛋白，导致转化。因此，病毒转化蛋白和融合癌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 蛋白与 CBP 结合表明它们可能靶向前列腺中的转录共激活因子 (CBP/p300) 癌细胞导致多种信号转导途径失调，包括调节细胞凋亡。这些观察结果表明，过度表达的 erg 蛋白以 CBP 为目标，导致前列腺癌细胞导致转化。因此，我们假设高水平的 erg 可能与 CBP 竞争，导致 CBP 介导的类维生素A转录激活特性受到抑制 X 受体（RXR α）。由于 RXR α 的转录激活特性对于细胞凋亡至关重要， erg 可能干扰 RXR α/CBP 介导的细胞凋亡的假设是合理的。这假设将在体外和体内进行测试。这些研究不仅能解释分子人类前列腺癌中 erg 基因的激活机制，也为治疗提供线索干涉。