Retinoic acid and CRABP-II in regulation of post transcriptional gene silencing

视黄酸和 CRABP-II 在转录后基因沉默调控中的作用

• 批准号: 9020212
• 负责人: DONNA M DRISCOLL
• 金额: $ 32.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020212
• 关键词: Affinity; Animals; Apoptosis; Apoptotic; Basic Science; Binding; Binding Proteins; Biological; Biological Process; Biology; Breast Carcinoma; Caspase; Cell Cycle Arrest; Cell Nucleus; Cell Proliferation; Cell Proliferation Regulation; Cell Survival; Cell physiology; Cells; Chemopreventive Agent; Complex; Cytosol; Data; Drosophila genus; Family; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Health; Ligands; Ligation; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Messenger RNA; Molecular; Nuclear; Nuclear Receptors; Property; Proteins; RNA Interference; Regulation; Research Design; Role; Stimulus; Transcript; Tretinoin; Tumor Suppressor Proteins; Vitamin A; Work; activating transcription factor; base; biophysical properties; cancer cell; cancer therapy; cell growth; cellular retinoic acid binding protein II; design; insight; mRNA Stability; man; member; new therapeutic target; non-genomic; novel; receptor; response; transcription factor

DESCRIPTION (provided by applicant): The vitamin A metabolite all-trans-retinoic acid (RA) displays potent anticarcinogenic activities and is used clinically for treatment of some cancers. I is well established that RA inhibits carcinoma cell growth by activating RAR, a member of the nuclear receptor family of ligand-activated transcription factors. Activation of RAR by RA is supported by cellular RA-binding protein II (CRABP-II), a small soluble protein which, by delivering RA from the cytosol to nuclear RAR, facilitates the ligation of the receptor and enhances its transcriptional activity. Previous studies established that CRABP-II functions as a tumor suppressor in various cancers including mammary and prostate cancers. Intriguingly, our recent observations showed that, in addition to its established role as a carrier for RA, CRABP-II is involved in regulation of post-transcriptional gene silencing. The data demonstrated that CRABP-II directly associates with HuR, the best characterized regulator of transcript stability in animals from drosophila to man, and that it markedly augments the ability of HuR to stabilize target mRNAs. The observations showed further that the CRABP-II?HuR complex dissociates in response to RA. These findings reveal a novel RA-controlled activity of CRABP-II. The proposed studies aim to investigate the molecular basis for the cooperation of CRABP-II with HuR in stabilizing mRNA, and to explore the involvement of this cooperation in mammary carcinoma biology. The results of these studies will provide important insights into a previously unsuspected non-genomic function of RA as well as into a novel mechanism for regulating transcript stability in cells. The studies will also investigate the possibility that suppression o mammary carcinoma growth by CRABP-II is mediated in part through the ability of the protein to regulate mRNA stability.

描述（由申请人提供）：维生素A代谢产物全反式反激酸（RA）显示出有效的抗癌活性，并在临床上用于某些癌症治疗。我已经很好地确定RA可以通过激活RAR（RAR）抑制癌细胞的生长，RAR是配体激活的转录因子的核受体家族的成员。 RA的RAR激活得到了细胞RA结合蛋白II（CrabP-II）的支持，这是一种小型可溶性蛋白，通过将RA从胞质醇传递到核RAR，可以促进受体的连接并增强其转录活性。先前的研究表明，CrabP-II在包括乳腺和前列腺癌在内的各种癌症中充当肿瘤抑制剂。有趣的是，我们最近的观察结果表明，除了其作为RA的携带者的确定作用外，CrabP-II还参与了转录后基因沉默的调节。数据表明，CrabP-II与HUR直接相关联，这是从果蝇到人的动物中最佳特征的转录物稳定性调节剂，并且显着增强了HUR稳定目标mRNA的能力。该观察结果进一步表明，Crabp-ii？hur复合物响应RA。这些发现揭示了CrabP-II的新型RA控制活性。拟议的研究旨在研究CrabP-II与HUR在稳定mRNA方面合作的分子基础，并探索这种合作参与乳腺癌生物学。这些研究的结果将为RA的先前未经引起的非基因组功能以及调节细胞中转录稳定性的新机制提供重要的见解。这些研究还将调查CrabP-II抑制O乳腺癌生长的可能性，部分是通过蛋白质调节mRNA稳定性的能力来介导的。