Functional role of Erg in prostate cancer

Erg 在前列腺癌中的功能作用

• 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
• 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

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、克隆和鉴定了人类erg（ets相关基因）基因， 表明它编码序列特异性转录激活因子。Erg基因参与尤因家族 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 提示这种抗凋亡功能可能在转化中起作用。Erg基因也被证明是 在大多数人前列腺中与前列腺特异性雄激素调节基因TMPRSS 2融合 导致ERG过度表达的癌症。美国的非洲裔美国人受到 与白色男性相比，前列腺癌的发病率不成比例。因此，研究erg在 对于发展未来的治疗策略和减少健康风险， 在非裔美国男性中的差异。观察到erg相关蛋白、Fli-1和EWS-Fli-1在细胞内表达， 靶向CBP样E1 A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蛋白结合CBP，表明它们可能靶向前列腺中的转录共激活因子（CBP/p300）。 导致多种信号转导途径失调的癌细胞， 凋亡这些观察结果表明，过度表达的erg蛋白靶向CBP，导致CBP的存活。 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CBP介导的类维生素A转录激活特性的抑制 X受体（RXR α）。由于RXR α的转录激活特性对细胞凋亡至关重要， 推测erg可能干扰RXR α/CBP介导凋亡是合理的。这 假设将在体外和体内进行检验。这些研究不仅能解释 erg基因在人前列腺癌中激活机制，也为前列腺癌的治疗提供了线索 干预