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，增殖增加和细胞凋亡减少。已知调控所有这些过程的转录调节因子家族是分化抑制（Id）蛋白（Id1, Id2， Id3和Id4）家族。Id蛋白主要作为基本螺旋环螺旋（bHLH）蛋白活性的显性负调节因子，但也可以调节Ets、PAX和Rb等非bHLH蛋白的活性。因此，在未分化的肿瘤细胞中，Id基因表达升高，支持其作为分化抑制因子和生长促进因子的作用。Id1表达的增加也与前列腺癌分级的增加有关。我们最近的研究表明，Id1和Id3启动原代前列腺上皮细胞的永生化，促进侵袭性，其缺失可阻断前列腺癌细胞的增殖。鉴于这一关键作用，Id基因被认为是前列腺癌的诊断标记和治疗靶点。尽管具有这一意义，但Id基因作用的潜在分子机制尚不清楚。例如，Id1和Id3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，该提案旨在验证我们的第一个假设，即“Id1和Id3通过作为独特的促肿瘤和抗肿瘤途径的调节因子来促进PCa”。我们最近的研究也表明，Id4作为肿瘤抑制因子，与肿瘤启动子Id1-3相比，其功能不同。Id4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“Id4可能通过调节信号通路或改变转录程序来作为肿瘤抑制因子”。非重叠的异构体特异性功能清楚地表明，由Id基因引发的下游事件是独特的，需要确定。了解这些Id蛋白的分子作用机制将对确定这些蛋白在PCa中的作用及其整体生物学意义重大。提出以下具体目的：1)检测Id1-4在前列腺中的表达；2)探讨Id1/3在前列腺癌中表达升高的意义；3)确定Id4的分子作用机制。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亚型作为诊断标记和治疗靶点的意义。新出现的假设是，在PCa中，Id亚型具有独特的功能，在多个水平上整合了它们的促肿瘤和抗肿瘤途径。

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.