Nuclear receptors function to transduce hormonal signals into transcription responses. Many of these receptors require dimerization with the retinoid receptor X (RXR), suggesting extensive interaction of vitamin A with many hormonal signals. However, for receptors without known ligands (orphan receptors), critical questions are what kind of signaling pathways do orphan receptors represent and what roles do they play in vitamin A biology. This lab has recently characterized an orphan receptor family TR2/TR4 which are specifically elevated in developing germ cells and able to modulate retinoic acid (RA) signals in several experimental systems. Based upon our preliminary studies, it is hypothesized that this orphan receptor family members function to modulate vitamin A signaling pathways by both active and passive mechanisms. Additionally, it is hypothesized that the active silencing mechanism is mediated by its ligand binding domain which encodes a trans-repressive activity and involves an interacting protein RIP140 that cross-talks with retinoic acid receptors RARs and RXRs. The passive mechanism is mediated by forming their own homo- or hetero-dimers within this family, which competes with RAR/RXR for DNA target sites. This proposal will test these hypotheses by asking three questions in three aims. 1) What is the molecular basis of the active silencing activity of TR2 that involves the interaction with RIP140? 2) What underlies the ability of TR2 and TR4 (but not RXR) hetero-dimerization? 3) Does TR2 and TR4 dimers (homo- and hetero-) efficiently compete for DNA binding sites with receptor dimers involving RARs or RXRs. Molecular and biochemical approaches will be taken to address these questions. We hope to extend our understanding of nuclear receptor functions in general, to provide a molecular explanation for the functions of orphan receptors without known hormonal signals, and to understand specifically how TR2 family members cross-talk with vitamin A for specific gene regulation. Ultimately, these studies will provide a model to address how vitamin A interacts with specific cellular factors and exerts its functions, and how the efficacy of vitamin A, as a therapeutic agent or a nutrient, may be modulated by specific cellular factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054733-04
Application #
6523746
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$192,298
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Park, Sung Wook; Persaud, Shawna D; Ogokeh, Stanislas et al. (2018) CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling. J Endocrinol 236:151-165
Lin, Yu-Lung; Tsai, Hong-Chieh; Liu, Pei-Yao et al. (2017) Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response. Cell Death Dis 8:3203
Lee, Bomi; Iwaniec, Urszula T; Turner, Russell T et al. (2017) RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis. JCI Insight 2:e90517
Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2017) Post-Transcriptional Regulation of the Human Mu-Opioid Receptor (MOR) by Morphine-Induced RNA Binding Proteins hnRNP K and PCBP1. J Cell Physiol 232:576-584
Lin, Yu-Lung; Persaud, Shawna D; Nhieu, Jennifer et al. (2017) Cellular Retinoic Acid-Binding Protein 1 Modulates Stem Cell Proliferation to Affect Learning and Memory in Male Mice. Endocrinology 158:3004-3014
Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na et al. (2017) Epigenetic Activation of ?-Opioid Receptor Gene via Increased Expression and Function of Mitogen- and Stress-Activated Protein Kinase 1. Mol Pharmacol 91:357-372
Heisel, Timothy; Montassier, Emmanuel; Johnson, Abigail et al. (2017) High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut. mSphere 2:
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2017) Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP). Gene 598:113-130
Lee, Bomi; Wu, Cheng-Ying; Lin, Yi-Wei et al. (2016) Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling. Nucleic Acids Res 44:7568-79
Wu, Cheng-Ying; Persaud, Shawna D; Wei, Li-Na (2016) Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation. Stem Cells 34:114-23

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