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.
The vitamin A metabolite all-trans-retinoic acid (RA) displays potent anticarcinogenic activities and is used clinically for treatment of some cancers. It is well established that RA inhibits carcinoma cell growth by regulating gene transcription, a function exerted through activation of the transcription factor termed RAR. Activation of RAR by RA is supported by cellular RA-binding protein II (CRABP-II), a protein that directly delivers RA from the cytosol to nuclear RAR. 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, and that it does so by cooperating with HuR, the best characterized regulator of mRNA stability in animals from drosophila to man. The proposed studies are designed to explore the possibility that anticarcinogenic activities of CRABP-II and RA are mediated in part through their involvement in regulating mRNA stability. The 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. At the level of basic science, 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 findings of this work may also point at a novel target for therapeutic approaches in cancer treatment.
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