Retinoid Tumor Differentiation Mechanisms

类维生素A肿瘤分化机制

• 批准号: 7406052
• 负责人: MICHAEL J SPINELLA
• 金额: $ 24.86万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406052
• 关键词: Acute; Affect; Agonist; Appendix; Area; Binding; Biochemical; Breast Cancer Cell; Cancer Biology; Carcinoma; Cell Cycle Arrest; Cell Differentiation process; Cells; Class; Clinical; Complex; Embryonal Carcinoma; Engineering; Estrogen Antagonists; Estrogens; Family member; Feedback; G1 Arrest; Gene Activation; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Hormonal; Hormone Receptor; Hormones; Human; Ligands; Link; Mammary Neoplasms; Mediating; Microarray Analysis; Modeling; Nuclear Receptors; Pathway interactions; Phenotype; Play; Prevention; Protein Overexpression; RXR; Range; Receptor Signaling; Regulation; Retinoic Acid Response Element; Retinoid Receptor; Retinoids; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; System; Testing; Transcriptional Regulation; Tretinoin; Tumor Tissue; Tumorigenicity; Up-Regulation; base; cancer therapy; design; human NRIP1 protein; insight; malignant breast neoplasm; member; neoplastic cell; novel; nuclear receptor co-repressor; prevent; programs; promoter; receptor; response; tumor

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，类维生素A在预防或治疗临床肿瘤方面具有有益的作用。类维生素A是通过激活类维生素A受体而确定的基因转录调节剂。类维生素A受体的关键靶点尚不清楚。我们已经发现了一种具有潜在重大生物学意义的新途径，该途径预计可在受体水平上调节类维生素A信号传导，并提供类维生素A与其他核受体家族成员之间的串扰。我们前期的基因芯片研究发现，核受体辅阻遏物受体相互作用蛋白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辅助调节因子，因为它能够抑制各种激动剂结合的激素受体的功能。 我们建议，RIP140的激活可能是一个通用的机制，调节RA介导的G1期阻滞在不同的细胞环境中，通过抑制核受体家族成员之间的串扰机制。基于新的初步发现，我们设计了三个具体的目标，以确定RIP140是否在类维生素A癌症生物学的两个临床重要领域中发挥关键作用。在RA诱导的人类胚胎癌的终末分化过程中，我们将询问RA对RIP140的调节是否构成了一种程序化的负反馈机制，限制了类维生素A受体的激活。在第二个系统中，我们将询问RIP140是否介导人类乳腺癌中类维生素A和雌激素信号之间的串扰。待检验的新假设是，类维生素A调节基因表达和生物表型的一种机制是通过直接激活类维生素A靶基因RIP140进行反式阻遏。这三个特定的目的是为了探索RA诱导RIP140的机制后果，并确定RIP140是否在调节类维生素A诱导的肿瘤细胞分化和G1期阻滞中发挥核心作用。我们相信RIP140是一个很好的切入点，可以获得关于辅调节因子动力学在广泛的激素，肿瘤和组织中激素信号传导中的作用的机制见解。

项目成果

Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.

RIP140在诱导多能人类胚胎癌细胞的肿瘤细胞分化过程中对视黄酸靶基因的选择性抑制。

• DOI: 10.1186/1476-4598-6-57
• 发表时间: 2007-09-19
• 期刊: MOLECULAR CANCER
• 影响因子: 37.3
• 作者: Heim, Kelly C;White, Kristina A;Deng, Dexin;Tomlinson, Craig R;Moore, Jason H;Freemantle, Sarah J;Spinella, Michael J
• 通讯作者: Spinella, Michael J

Headway and hurdles in the clinical development of dietary phytochemicals for cancer therapy and prevention: lessons learned from vitamin A derivatives.

用于癌症治疗和预防的膳食植物化学物质临床开发的进展和障碍：维生素 A 衍生物的经验教训。

• DOI: 10.1208/s12248-014-9562-2
• 发表时间: 2014
• 期刊: The AAPS journal
• 作者: Yim,ChristinaY;Mao,Pingping;Spinella,MichaelJ
• 通讯作者: Spinella,MichaelJ