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This version published online on December 29, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0209
A more recent version of this article appeared on April 1, 2005
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Submitted on May 20, 2004
Accepted on December 20, 2004

Negative Cross-talk between Nur77 and SHP and Its Role in Apoptotic Cell Death of Hepatoma Cells

Myeong Goo Yeo, Young-Gun Yoo, Heung-Sik Choi, Youngmi Kim Pak, and Mi-Ock Lee*

Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea (M.G.Y., Y.-G. Yoo, M.-O.L.) and Hormone Research Center, Chonnam National University, Kwangju 138-736, Korea (H.-S.C.); Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 500-757, Korea (Y.K.P.)

* To whom correspondence should be addressed. E-mail: molee{at}sejong.ac.kr.

Nur77, an orphan nuclear receptor, has been implicated in apoptosis of a variety of cell types, including hepatocytes. The small heterodimer partner (SHP) binds and inhibits the function of many nuclear receptors. Here, we investigated cross-talk between Nur77 and SHP during anti-Fas antibody (CH11)-mediated apoptosis of hepatic cells. Expression of SHP decreased, whereas anti-sense SHP enhanced, the transcriptional activity of Nur77 in HepG2 cells. SHP and Nur77 were physically associated in vivo and co-localized in the nucleus. SHP decreased the transactivation function of the N-terminal domain of Nur77 that recruits coactivators. Nur77 and SHP competitively bound to CREB-binding protein (CBP) and the expression of coactivators, such as CBP and ASC-2, recovered the decreased function of Nur77 caused by SHP. Finally, SHP was differentially expressed in hepatoma cell lines in that it was not detected in the IFN{gamma}/CH11 sensitive SNU354, whereas it was significantly expressed in the IFN{gamma}/CH11 resistant HepG2. Interestingly, a stable SNU354 cell line that expressed SHP became resistant to the IFN{gamma}/CH11-induced apoptosis. Together, our results suggest that SHP plays a key role in the regulation of Nur77 activation and thereby in Nur77-mediated apoptosis in the liver.


Key words: Nur77 • SHP • apoptosis • liver

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  NGFIB  |  NURR1  |  NOR1
Coregulators:   PGC-1  |  CBP  |  p300  |  ASC-2



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