Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPalpha.
SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761-49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158-23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; -99 to -76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPalpha activation.
Park
Min Jung
MJ
Department of Molecular Biology, Pusan National University, Busan 609-735, Korea.
Kong
Hee Jeong
HJ
Kim
Hye Young
HY
Kim
Hyeong Hoe
HH
Kim
Joon Hong
JH
Cheong
Jae Hun
JH
D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D005943:Gluconeogenesis / Q000235:genetics*; D006801:Humans; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051818:Replication Protein C / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D022763:CCAAT-Enhancer-Binding Protein-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA; D051818:Replication Protein C; D019764:Phosphoenolpyruvate Carboxykinase (ATP)