The orphan receptor SHP is an unusual member of the nuclear superfamily that lacks a DNA binding domain. It interacts functionally with many other superfamily members, including both conventional receptors and orphans. It generally inhibits transactivation, but can be stimulatory in specific circumstances. Insight into the potential function of SHP was recently provided by exciting results demonstrating that an unusual group of Japanese patients with mature onset diabetes of the young (MODY) are heterozygous for SHP gene mutations. Particularly since one of the five known MODY genes encodes the orphan receptor HNF4, which a specific inhibitory target of SHP, it is hypothesized that SHP acts with HNF4 or potentially other transcription factors to regulate the normal glucose response of pancreatic beta cells. More broadly, HNF4 and other potential SHP targets have profoundly important developmental functions, and it is hypothesized that complete loss of SHP function will also have important consequences for development.
Three specific aims are proposed to test these hypotheses. The first is to characterize in detail the interaction between SHP and HNF4, and to determine whether SHP also interactions functionally with the three other MODY transcription factors. The second is to determine the consequences of the loss of SHP function in the embryoid body model of endoderm development, particularly its effects on the HNF4/HNF1 regulatory hierarchy. The third is to inactive the SHP gene in mice by knocking in the beta-galactosidase gene, and also to determine whether SHP acts positively or negatively in the pancreas and other tissues using a novel transgenic activity trap. These studies will provide novel insights into the role of SHP in both metabolic and developmental regulatory pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK057743-01
Application #
6324284
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (J3))
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$177,233
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Demayo, Janet L; Wang, Jie; Liang, Dongcai et al. (2012) Genetically Engineered Mice by Pronuclear DNA microinjection. Curr Protoc Mouse Biol 2:245-262
Huang, Jiansheng; Iqbal, Jahangir; Saha, Pradip K et al. (2007) Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 46:147-57
Wang, Li; Huang, Jiansheng; Saha, Pradip et al. (2006) Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis. Mol Endocrinol 20:2671-81
Wang, Li; Liu, Jun; Saha, Pradip et al. (2005) The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab 2:227-38
Gu, Peili; Goodwin, Bryan; Chung, Arthur C-K et al. (2005) Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol 25:3492-505
Lee, Christopher T; Li, Luoping; Takamoto, Norio et al. (2004) The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Mol Cell Biol 24:10835-43
Zhou, Ge; Hashimoto, Yoshihiro; Kwak, Inseok et al. (2003) Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol 23:7742-55
Wang, Li; Han, Yunqing; Kim, Chang-Soo et al. (2003) Resistance of SHP-null mice to bile acid-induced liver damage. J Biol Chem 278:44475-81
Ponnio, Tiia; Burton, Quiana; Pereira, Fred A et al. (2002) The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol 22:935-45
Takamoto, Norio; Zhao, Bihong; Tsai, Sophia Y et al. (2002) Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus. Mol Endocrinol 16:2338-48

Showing the most recent 10 out of 14 publications