Retinoid Tumor Differentiation Mechanisms

类维生素A肿瘤分化机制

• 批准号: 6906395
• 负责人: MICHAEL J SPINELLA
• 金额: $ 26.22万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906395
• 关键词: all trans retinol; biological signal transduction; breast neoplasms; cell cycle; cell differentiation; estrogens; gene expression; gene targeting; germ cell neoplasms; microarray technology; neoplasm /cancer pharmacology; neoplastic growth; nuclear proteins; nuclear receptors; protein protein interaction; transfection /expression vector

DESCRIPTION (provided by applicant): There is rapidly evolving evidence for beneficial retinoid actions in preventing or treating clinical tumors. Retinoids are established regulators of gene transcription via activation of retinoid receptors. The key targets of retinoid receptors are unknown. We have discovered a novel pathway of potential major biologic significance that is predicted to regulate retinoid signaling at the level of the receptor and also to provide cross-talk between retinoids and other nuclear receptor family members. Our previous microarray studies discovered that the nuclear receptor co-repressor, receptor interacting protein 140 (RIP140) is a novel direct target of all-trans retinoic acid (RA). RIP140 appears to belong to a novel class of nuclear receptor coregulators since it is able to suppress the function of various agonist-bound hormone receptors. We propose that the activation of RIP140 may be a general mechanism that regulates RA-mediated G1 arrest in diverse cell contexts through a mechanism of repressional cross-talk among nuclear receptor family members. Based on novel preliminary findings we have designed three specific aims that will establish whether RIP140 plays a critical role in two clinically important areas of retinoid cancer biology. During RA-induced terminal differentiation of human embyronal carcinoma, we will ask whether RA regulation of RIP140 constitutes a programmed negative feedback mechanism which limits the activation of retinoid receptors. In the second system, we will ask whether RIP140 mediates cross-talk between retinoid and estrogen signaling in human breast cancer. The novel hypothesis to be tested is that one mechanism by which retinoids regulate gene expression and biologic phenotype is by transrepression through direct activation of the retinoid target gene RIP140. The three specific aims are designed to probe the mechanistic consequence of RA induction of RIP140 and to establish whether RIP140 plays a central role in regulating retinoid-induced tumor cell differentiation and G1 arrest. We believe RIP140 is an excellent entry point to gain mechanistic insights on the role of coregulator dynamics in hormonal signaling across a broad range of hormones, tumors and tissues.

描述(由申请人提供)：有快速发展的证据表明，维甲酸在预防或治疗临床肿瘤中具有有益的作用。维甲酸是通过激活维甲酸受体来调节基因转录的物质。维甲酸受体的关键靶点尚不清楚。我们已经发现了一条具有潜在重要生物学意义的新途径，预计它将在受体水平上调节维甲酸信号，并在维甲酸与其他核受体家族成员之间提供串扰。我们以前的基因芯片研究发现，核受体共抑制因子受体相互作用蛋白140(RIP140)是全反式维甲酸(RA)的一个新的直接靶点。RIP140似乎属于一类新的核受体共调节因子，因为它能够抑制各种激动剂结合的激素受体的功能。 我们认为，RIP140的激活可能是在不同的细胞环境中通过核受体家族成员之间的抑制性串扰机制来调节RA介导的G1期停滞的一般机制。基于新的初步发现，我们设计了三个特定的目标，以确定RIP140是否在两个临床重要的维甲类癌症生物学领域发挥关键作用。在RA诱导人胚胎癌细胞终末分化的过程中，我们会问RA对RIP140的调节是否构成了一种程序性负反馈机制，限制了维甲酸受体的激活。在第二个系统中，我们将询问RIP140是否在人类乳腺癌中介导维甲酸和雌激素信号之间的串扰。有待检验的新假设是，维甲酸调节基因表达和生物学表型的机制之一是通过直接激活视黄素靶基因RIP140进行转录抑制。这三个特定的目的旨在探讨RIP140诱导RA的机制后果，并确定RIP140是否在调节维甲酸诱导的肿瘤细胞分化和G1期停滞中发挥核心作用。我们相信，RIP140是一个很好的切入点，可以从机制上深入了解协同调节动力学在广泛的激素、肿瘤和组织中的激素信号传递中所起的作用。