Inhibitor of Differentiation Gene Expression and Function in Prostate Cells

前列腺细胞分化基因表达和功能的抑制剂

• 批准号: 8193159
• 负责人: JAIDEEP CHAUDHARY
• 金额: $ 27.79万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193159
• 关键词: Address; Adult; Apoptosis; Apoptotic; BHLH Protein; Biology; Cancer Biology; Carcinoma; Cells; Diagnostic; Differentiation Inhibitor; Differentiation and Growth; Disease Progression; Dominant-Negative Mutation; Epithelial Cells; Epithelium; Event; Family; Gene Expression; Genes; Goals; Health; Helix-Turn-Helix Motifs; Heterogeneity; Human; Inhibitor of Differentiation Proteins; Intervention; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Molecular Mechanisms of Action; Mus; Mutation; Neoplasm Metastasis; Nude Mice; Pathway interactions; Principal Investigator; Process; Property; Prostate; Protein Isoforms; Proteins; Regulation; Research; Role; Signal Pathway; Structure-Activity Relationship; Testing; Therapeutic Intervention; Tumor Promoters; Tumor Suppressor Proteins; Undifferentiated; base; cancer cell; cancer initiation; design; gene function; genetic regulatory protein; in vivo; inhibitor/antagonist; loss of function; mouse model; neoplastic cell; programs; therapeutic target; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：前列腺上皮的转化以及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（Id1、Id2、Id3 和 Id4）家族。 Id 蛋白主要充当碱性螺旋环螺旋 (bHLH) 蛋白活性的显性负调节因子，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，支持其作为分化抑制剂和生长促进因子的作用。 Id1 表达的增加也与 PCa 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，并且 Id1 和 Id3 的缺失会阻止 PCa 细胞的增殖。鉴于这一关键作用，Id 基因被认为是 PCa 的诊断标记和治疗靶点。尽管具有如此重要的意义，但 Id 基因作用的潜在分子机制尚不清楚。例如，Id1 和 Id3 是否具有重叠功能或针对独特的促肿瘤和/或抗肿瘤途径？因此，该提案旨在检验我们的第一个假设：“Id1 和 Id3 通过充当独特的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，Id4 充当肿瘤抑制因子，其功能与肿瘤促进剂 Id1-3 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，我们提出了第二个假设：“Id4 可能通过调节信号通路或改变转录程序来充当肿瘤抑制因子”。非重叠的同种型特异性功能清楚地表明，Id 基因引发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对于定义这些蛋白在 PCa 中的作用及其整体生物学具有重要意义。提出以下具体目标：1) 检查前列腺中 Id1-4 的表达，2) 研究 PCa 中 Id1/3 表达增加的意义，3) 确定 Id4 作用的分子机制。完成这些研究将使我们能够更好地理解：a) PCa 启动/维持所涉及的分子机制 b) Id 蛋白的生物学和 c) Id 同工型作为诊断标志物和治疗靶点的重要性。新出现的假设是，Id 同工型具有独特的功能，可以在 PCa 的多个水平上整合其促肿瘤和抗肿瘤途径。 公共健康相关性：本研究的目的是了解转录调节因子 Id（分化抑制剂）家族在前列腺癌发生和进展中的作用。该提案的结果证明了 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使用 Id 基因本身作为治疗靶点。