Negative cross-talk between Nur77 and small heterodimer partner and its role in apoptotic cell death of hepatoma cells.
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 antisense SHP enhanced, the transcriptional activity of Nur77 in HepG2 cells. SHP and Nur77 were physically associated in vivo and colocalized in the nucleus. SHP decreased the transactivation function of the N-terminal domain of Nur77 that recruits coactivators. Nur77 and SHP competitively bound to cAMP response element-binding protein-binding protein and the expression of coactivators, such as cAMP response element-binding protein-binding protein and activating signal cointegrator-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 interferon-gamma (IFNgamma)/CH11-sensitive SNU354, whereas it was significantly expressed in the IFNgamma/CH11-resistant HepG2. Interestingly, a stable SNU354 cell line that expressed SHP became resistant to the IFNgamma/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.
Yeo
Myeong Goo
MG
College of Pharmacy, Seoul National University, San 56-1 Sillim, Kwanak, Seoul 151-742, Korea.
Yoo
Young-Gun
YG
Choi
Hueng-Sik
HS
Pak
Youngmi Kim
YK
Lee
Mi-Ock
MO
D017209:Apoptosis; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D056918:Nuclear Receptor Coactivators; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C486559:NCOA6 protein, human; C539821:NR4A1 protein, human; D056918:Nuclear Receptor Coactivators; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012097:Repressor Proteins; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2