Functional role of Erg in prostate cancer

Reddy和他的同事们已经识别、克隆和表征了人类erg(ETS相关基因)基因和 表明它编码序列特异的转录激活子。Erg基因与尤因家族有关 肿瘤和人类髓系白血病。ERG和异常的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过程中发挥作用。Erg基因也被证明是 与前列腺特异性雄激素调节基因TMPRSS2在大多数人前列腺中的融合 导致erg过度表达的肿瘤。在美国的非裔美国男性受到 与白人男性相比，前列腺癌的人数不成比例。因此，研究ERG在生物信息学中的作用 前列腺癌对开发未来的治疗策略和减少健康具有重要意义 非裔美国男性之间的差异。观察到ERG相关蛋白、Fli-1和EWS-Fli-1 靶向CBP样癌蛋白E1a，导致转化。因此，病毒转化蛋白与融合 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结合提示它们可能针对前列腺中的转录辅助激活因子(CBP/p300) 癌细胞导致多个信号转导通路的放松调控，包括调节 细胞凋亡。这些观察结果表明，过度表达的erg蛋白靶向CBP，导致肝癌存活。 导致前列腺癌细胞转化。因此，我们假设高水平的ERG可能 BE竞争CBP导致抑制CBP介导的维甲酸转录激活特性 X受体(RXRα)。由于RXRα的转录激活特性对细胞凋亡是必不可少的， 推测ERG可能干扰RXRα/CBP介导的细胞凋亡是合理的。这 假说将在体外和体内进行检验。这些研究将不仅解释分子上的 ERG基因在前列腺癌中的激活机制为治疗提供线索 干预。

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.