Inhibitor of Differentiation Gene Expression and Function in Prostate Cells

描述（由申请人提供）：前列腺上皮的转化和向浸润性癌的进展涉及分化过程的失调、增殖增加和凋亡减少。已知调节所有这些过程的转录调节因子家族是分化抑制剂（Id）蛋白（Id 1、Id 2、Id 3和Id 4）家族。Id蛋白主要作为碱性螺旋环螺旋（bHLH）蛋白活性的显性负调节剂起作用，但也可以调节非bHLH蛋白如Ets、PAX和Rb的活性。因此，Id基因表达在未分化的肿瘤细胞中升高，支持它们作为分化抑制剂和生长促进因子的作用。Id 1表达增加也与PCa分级增加相关。我们最近的研究表明，Id 1和Id 3启动原代前列腺上皮细胞的永生化，促进侵袭性，其缺失阻断PCa细胞的增殖。鉴于这一关键作用，Id基因被认为是PCa的诊断标志物和治疗靶点。尽管有这种意义，Id基因作用的潜在分子机制还远不清楚。例如，Id 1和Id 3是否具有重叠的功能或靶向独特的促肿瘤和/或抗肿瘤途径？因此，该提案旨在测试我们的第一个假设，即“Id 1和Id 3通过充当独特促肿瘤和抗肿瘤途径的调节剂来促进PCa”。我们最近的研究还表明，Id 4作为一种肿瘤抑制因子，其功能与肿瘤促进因子Id 1 -3不同。Id 4这种独特功能的分子基础是什么？为了解决这个问题，我们提出了我们的第二个假设，即“Id 4可能作为一个肿瘤抑制因子，通过调节信号通路或通过改变转录程序”。非重叠的同种型特异性功能清楚地表明，由Id基因引起的下游事件是独特的，需要确定。了解Id蛋白的这些分子作用机制将对确定这些蛋白在PCa及其整体生物学中的作用具有重要意义。本研究的主要目的是：1）检测Id 1 -4在前列腺中的表达; 2）研究Id 1/3在前列腺癌中表达增加的意义; 3）确定Id 4作用的分子机制。这些研究的完成将使我们能够更好地理解：a）参与PCa启动/维持的分子机制B）Id蛋白的生物学和c）Id亚型作为诊断标志物和治疗靶点的意义。新出现的假设是Id亚型具有独特的功能，在PCa中多个水平整合其促肿瘤和抗肿瘤途径。 公共卫生相关性：该研究的目的是了解Id（分化抑制剂）家族转录调节因子在前列腺癌发生和发展中的作用。该提案的结果表明Id基因在前列腺癌中的表达和作用机制将有助于决定治疗干预策略和Id基因本身作为治疗靶点的用途。

DESCRIPTION (provided by applicant): The transformation of the prostate epithelium, and progression to invasive carcinoma, involves de-regulation of the differentiation process, increased proliferation and decrease in apoptosis. A family of transcriptional regulators, known to regulate all these processes, is the Inhibitor of differentiation (Id) protein (Id1, Id2, Id3 and Id4) family. The Id proteins primarily function as dominant negative regulators of basic helix loop helix (bHLH) protein activity but can also modulate the activity of non-bHLH proteins such as Ets, PAX and Rb. Consequently, Id gene expression is elevated in undifferentiated tumor cells, supporting their role as inhibitors of differentiation and growth promoting factors. Increased Id1 expression is also associated with increasing grade of PCa. Our recent studies demonstrate that Id1 and Id3 initiates immortalization of primary prostate epithelial cells, promotes aggressiveness and its loss blocks proliferation of PCa cells. Given this critical role, the Id genes are considered as diagnostic markers and therapeutic targets in PCa. In spite of this significance, the underlying molecular mechanism of action of Id genes is far from clear. For example, do Id1 and Id3 have over-lapping functions or target unique pro-tumor and/or anti-tumor pathways? This proposal was therefore designed to test our first hypothesis that"Id1 and Id3 promote PCa by acting as regulators of unique pro-tumor and anti-tumor pathways". Our recent studies have also shown that Id4 acts as a tumor suppressor, a function that is distinct as compared to tumor promoters Id1-3. What is the molecular basis of this unique function of Id4? In order to address this question, we propose our second hypothesis that "Id4 may act as a tumor suppressor by modulating the signaling pathways or by altering the transcriptional program". The non over-lapping isoform specific functions clearly suggest that the downstream events elicited by Id genes are unique that needs to be determined. Understanding these molecular mechanisms of action of Id proteins will have significant implications on defining the role of these proteins in PCa and their overall biology. The following specific aims are proposed: 1) Examine the expression of Id1-4 in prostate, 2) Investigate the significance of increased Id1/3 expression in PCa and 3) Determine the molecular mechanism of action of Id4. Completion of these studies will allow us to better understand: a) the molecular mechanisms involved in the initiation/ maintenance of PCa b) biology of Id proteins and c) the significance of Id isoforms as diagnostic markers and therapeutic targets. The emerging hypothesis addressed is that Id isoforms have unique functions that integrate their pro- and anti-tumor pathways at multiple levels in PCa. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to understand the role of Id (inhibitor of differentiation) family of transcriptional regulators in prostate cancer initiation and progression. The results from this proposal demonstrating the expression and mechanism of action of Id genes in prostate cancer will help decide therapeutic intervention strategies and use of Id genes themselves as therapeutic targets.