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: 8435941
• 负责人: NOA NOY
• 金额: $ 37.85万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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/8435941
• 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; 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; cancer cell; cancer therapy; cell growth; cellular retinoic acid binding protein; cellular retinoic acid binding protein II; design; insight; mRNA Stability; man; member; new therapeutic target; non-genomic; novel; public health relevance; 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代谢物全反式维甲酸（RA）显示出有效的抗癌活性，临床上用于治疗某些癌症。众所周知，RA通过激活RAR来抑制癌细胞的生长，RAR是配体激活转录因子的核受体家族成员。RA激活RAR是由细胞RA结合蛋白II （CRABP-II）支持的，这是一种小的可溶性蛋白，通过将RA从细胞质输送到核RAR，促进受体的连接并增强其转录活性。先前的研究证实，CRABP-II在包括乳腺癌和前列腺癌在内的多种癌症中具有肿瘤抑制作用。有趣的是，我们最近的观察表明，除了作为RA载体的既定作用外，CRABP-II还参与转录后基因沉默的调控。这些数据表明，CRABP-II与从果蝇到人类的动物中转录稳定性的最佳调节因子HuR直接相关，并且它显著增强了HuR稳定靶mrna的能力。观测结果进一步表明，CRABP-II？HuR复合物在RA反应中解离。这些发现揭示了一种新的ra控制的CRABP-II活性。本研究旨在探讨CRABP-II与HuR合作稳定mRNA的分子基础，并探讨这种合作在乳腺癌生物学中的作用。这些研究的结果将为类风湿关节炎以前未被怀疑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。这些研究还将探讨CRABP-II抑制乳腺癌生长的可能性，部分是通过该蛋白调节mRNA稳定性的能力介导的。