Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA binds to nuclear receptors, retinoic acid receptor (RAR) and retinoid receptor X (RXR), to regulate target gene expression by triggering recruitment of coregulators that act, primarily, through chromatin remodeling and modification on the regulatory regions of target genes. Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140) is a ligand-dependent co-repressor, i.e. it represses hormonal induction of target gene expression in a hormone-dependent manner. The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The proposal focuses on chromatin remodeling events orchestrated by RIP140 and coactivators that form complexes with hormone receptors, such as RIP140-RAR/RXR complex and coactivator-RAR/RXR complexes, as well as the biological significance of several newly identified post-translational modifications in the modulation of receptor/coregulator activities. Two questions will be addressed: 1) how does RIP140 function in hormone-induced chromatin remodeling? 2) How does protein modification regulate the biological activity of RIP140? Wild type and genetically modified cells, including RIP140-knockout (RIP-/-) and TRAP220-knockout (TRAP-/-) cells, as well siRNA mediated gene knockdown in P19 cells will be used as the principal experimental systems. Chromatin segments containing hormone response elements (HREs) will be the targets of examination to address mechanistic details in a physiologically relevant context. These studies will provide mechanistic insights into crosstalk of hormones (vitamin A and thyroid hormones) via coordinated formation of specific transcription factor complexes. These studies will also uncover potentially novel signals and cellular factors that are critical to cell differentiation program where vitamin A and other endocrine factors play vital roles. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases, the studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health.

Public Health Relevance

Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA functions by regulating target gene expression through chromatin remodeling that involves Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140). The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The current proposal focuses on the functional role of NRIP1 from a mechanistic stand point. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases. The studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060521-10
Application #
8242858
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2002-03-15
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$308,990
Indirect Cost
$100,719
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Lin, Yi-Wei; Liu, Pu-Ste; Adhikari, Neeta et al. (2015) RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 79:287-94
Feng, Xudong; Krogh, Kelly A; Wu, Cheng-Ying et al. (2014) Receptor-interacting protein 140 attenuates endoplasmic reticulum stress in neurons and protects against cell death. Nat Commun 5:4487
Flaisher-Grinberg, S; Tsai, H C; Feng, X et al. (2014) Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus. Brain Behav Immun 40:226-34
Wu, Cheng-Ying; Feng, Xudong; Wei, Li-Na (2014) Coordinated repressive chromatin-remodeling of Oct4 and Nanog genes in RA-induced differentiation of embryonic stem cells involves RIP140. Nucleic Acids Res 42:4306-17
Feng, X; Wu, C-Y; Burton, F H et al. (2014) *-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. Cell Death Differ 21:397-406
Persaud, Shawna D; Lin, Yi-Wei; Wu, Cheng-Ying et al. (2013) Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cell Signal 25:19-25
Ho, Ping-Chih; Tsui, Yao-Chen; Lin, Yi-Wei et al. (2012) Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCýý-PKCýý pathway. Mol Cell Endocrinol 351:176-83
Ho, Ping-Chih; Tsui, Yao-Chen; Feng, Xudong et al. (2012) NF-?B-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol 13:379-86
Wei, Li-Na (2012) Chromatin remodeling and epigenetic regulation of the CrabpI gene in adipocyte differentiation. Biochim Biophys Acta 1821:206-12
Ho, Ping-Chih; Wei, Li-Na (2012) Negative regulation of adiponectin secretion by receptor interacting protein 140 (RIP140). Cell Signal 24:71-6

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