Retinoids play key roles in regulating cell proliferation and differentiation and are used as therapeutic agents in clinical settings ranging from dermatological disorders to cancer. Signaling by these hormones is mediated by two classes of ligand-activated transcription factors, the retinoic acid- and the retinoid X-receptors (RAR and RXR), which are activated by all trans- and 9 cis-retinoic acids, respectively (RA and 9cra). Because of its unique ability to heterodimerize with other nuclear receptors, RCR is involved in multiple signaling pathways and is thus sometimes termed a 'master regulator'. RXR is also unique in that, in the absence of 9cRA, it sequesters itself into transcriptionally inactive tetramers. Hence, RXR acts as an 'auto-silencer', and the first step in its activation seems to compromise ligand-induced dissociation of tetramers into active dimers and monomers. This application proposes to delineate the roles of the oligomerization behavior of RxR and the presence of various cognate ligands in governing the distribution of RXR between the multiple molecular complexes in which it may be involved in vivo. The functional consequences of the physical-chemical properties of the various RCR-containing oligomers for the transcriptional activity of RXR in cells, and the possible functional outcomes of DNA-binding by RXR tetramers will then be explored. In addition to retinoid receptors, two intracellular binding proteins for RA (CRABP-I and CRABP-II) are known to exist. The exact roles of CRABPs in the biology of RA and the functional differences between the two isoforms are not well defined. Our recent studies suggest that CRABP-II, but not CRABP-1, directly 'channels' retinoic acid to RAR, thereby enhancing the transcriptional activity of this receptor. These observations point at a novel role for CRABP-II in regulating retinoid signaling. We propose to study the CRABP-II.RAR interactions that allow for channeling of RA between them, and to address the physiological significance of these interactions by investigating the effect of CRABP-II on RA-induced stem cell differentiation. Overall, these studies are designed to clarify the factors that modulate the multiple interactions of retinoic nuclear receptors and to obtain insights into the mechanisms by which signaling by retinoids is regulated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068150-07
Application #
6497753
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Mietz, Judy
Project Start
1995-09-30
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
7
Fiscal Year
2002
Total Cost
$265,245
Indirect Cost
Name
Cornell University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Yasmin, Rubina; Kannan-Thulasiraman, Padmamalini; Kagechika, Hiroyuki et al. (2010) Inhibition of mammary carcinoma cell growth by RXR is mediated by the receptor's oligomeric switch. J Mol Biol 397:1121-31
Kannan-Thulasiraman, Padmamalini; Seachrist, Darcie D; Mahabeleshwar, Ganapati H et al. (2010) Fatty acid-binding protein 5 and PPARbeta/delta are critical mediators of epidermal growth factor receptor-induced carcinoma cell growth. J Biol Chem 285:19106-15
Noy, Noa (2007) Ligand specificity of nuclear hormone receptors: sifting through promiscuity. Biochemistry 46:13461-7
Schug, Thaddeus T; Berry, Daniel C; Shaw, Natacha S et al. (2007) Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129:723-33
Sessler, Richard J; Noy, Noa (2005) A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II. Mol Cell 18:343-53
Yasmin, Rubina; Williams, Rebecca M; Xu, Ming et al. (2005) Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer. J Biol Chem 280:40152-60
Yasmin, Rubina; Yeung, Kay T; Chung, Richard H et al. (2004) DNA-looping by RXR tetramers permits transcriptional regulation ""at a distance"". J Mol Biol 343:327-38
Wu, Zhiping; Yang, Yanwu; Shaw, Natacha et al. (2003) Mapping the ligand binding pocket in the cellular retinaldehyde binding protein. J Biol Chem 278:12390-6
Manor, Danny; Shmidt, Elena N; Budhu, Anuradha et al. (2003) Mammary carcinoma suppression by cellular retinoic acid binding protein-II. Cancer Res 63:4426-33
Golovleva, Irina; Bhattacharya, Sanjoy; Wu, Zhiping et al. (2003) Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions. J Biol Chem 278:12397-402

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