The vitamin A metabolite retinoic acid (RA) regulates gene transcription by activating two members of the nuclear receptor family of ligand-activated transcription factors: the retinoic acid receptors (RARs) and the peroxisome proliferator activated receptor?? (PPAR?). The partitioning of RA between its receptors is controlled by the intracellular lipid binding proteins CRABP-II, which delivers the hormone to RAR, and FABP5, which shuttles it to PPAR?. Consequently, the relative expression levels of CRABP-II and FABP5 determine the pathway through which RA activates transcription, the spectrum of genes whose expression is regulated by RA, and the biological responses to this hormone in different cells. RA is thus closely involved in regulation of multiple biological activities in health and in disease states including cancer and the metabolic syndrome. Studies described in this application will investigate the involvement of RA and its binding proteins and nuclear receptors in adipocyte biology and in regulating mammary carcinoma growth. Specifically, we propose to: 1) understand how RA maintains the phenotype of preadipose cells and to examine whether inhibition of adipogenesis by RA contributes to the remarkable ability of the hormone to counteract diet-induced obesity;2) investigate the possibility that development of some cancers originates from improper RA signalling derived from dysregulation of the FABP5/CRABP-II ratio, especially arising from upregulation of FABP5 in tumors. We propose to shed light on the mechanisms that lead to increased expression of FABP5 in mammary tumors, examine whether FABP5 functions as an oncogene, and explore the possibility that downregulation of FABP5 will divert RA from PPAR? to RAR to inhibit tumor growth.

Public Health Relevance

The vitamin A metabolite retinoic acid (RA) regulates gene transcription by activating two types of transcription factors: the retinoic acid receptors (RARs) and the peroxisome proliferator activated receptor ? (PPAR?). The partitioning of RA between these receptors is controlled by two RA-binding proteins, CRABP- II, which delivers the hormone to RAR, and FABP5, which shuttles it to PPAR?. Hence, the relative expression levels of CRABP-II and FABP5 determine the pathway through which RA activates transcription, the spectrum of genes whose expression in regulated by RA, and the biological responses to this hormone in different cells. By activating its dual transcriptional pathways, RA is closely involved in regulation of multiple biological activities in health and in disease states including cancer an the metabolic syndrome. Studies described in this application will investigate how RA and its binding proteins and nuclear receptors regulate the formation of fat cells and the molecular mechanisms by which the hormone controls the growth of breast cancer cells. The results of these studies are expected to shed light on fundamental issues in vitamin A biology and to point at novel strategies for treatment of obesity-associate diseases and of some cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK060684-11
Application #
8370620
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Margolis, Ronald N
Project Start
2001-12-01
Project End
2016-07-31
Budget Start
2012-08-24
Budget End
2013-07-31
Support Year
11
Fiscal Year
2012
Total Cost
$380,725
Indirect Cost
$138,225
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Noy, Noa (2015) Signaling by retinol and its serum binding protein. Prostaglandins Leukot Essent Fatty Acids 93:7-Mar
Yu, Shuiliang; Levi, Liraz; Casadesus, Gemma et al. (2014) Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by decreasing anandamide levels and by activating the nuclear receptor peroxisome proliferator-activated receptor ?/? (PPAR?/?) in the brain. J Biol Chem 289:12748-58
Armstrong, Eric H; Goswami, Devrishi; Griffin, Patrick R et al. (2014) Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor ?/? (FABP5-PPAR?/?) signaling pathway. J Biol Chem 289:14941-54
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Vreeland, Amanda C; Yu, Shuiliang; Levi, Liraz et al. (2014) Transcript stabilization by the RNA-binding protein HuR is regulated by cellular retinoic acid-binding protein 2. Mol Cell Biol 34:2135-46
Levi, Liraz; Lobo, Glenn; Doud, Mary Kathryn et al. (2013) Genetic ablation of the fatty acid-binding protein FABP5 suppresses HER2-induced mammary tumorigenesis. Cancer Res 73:4770-80
Berry, Daniel C; Noy, Noa (2012) Signaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis. Biochim Biophys Acta 1821:168-76
Berry, Daniel C; DeSantis, David; Soltanian, Hooman et al. (2012) Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes 61:1112-21
Majumdar, Avijit; Petrescu, Anca D; Xiong, Yin et al. (2011) Nuclear translocation of cellular retinoic acid-binding protein II is regulated by retinoic acid-controlled SUMOylation. J Biol Chem 286:42749-57
Berry, Daniel C; Jin, Hui; Majumdar, Avijit et al. (2011) Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci U S A 108:4340-5

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