Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone

被引:100
作者
Lahuna, O
Rastegar, M
Maiter, D
Thissen, JP
Lemaigre, FP
Rousseau, GG [1 ]
机构
[1] Catholic Univ Louvain, Hormone & Metabol Res Unit, B-1200 Brussels, Belgium
[2] Catholic Univ Louvain, Christian Duve Inst Cellular Pathol, Diabet Unit, B-1200 Brussels, Belgium
关键词
D O I
10.1210/me.14.2.285
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
HNF-6 is a tissue-restricted transcription factor that participates in the regulation of several genes in liver. We reported earlier that in adult rats, HNF-6 mRNA concentration in liver drops to almost undetectable levels after hypophysectomy and returns to normal after 1 week of GH treatment. We now show that this results from a rapid effect of GH, and we characterize its molecular mechanism. In hypophysectomized rats, HNF-6 mRNAs increased within 1 h after a single injection of GH. The same GH-dependent induction was reproduced on isolated hepatocytes. To determine whether GH regulates hnf6 expression at the gene level, we studied its promoter. DNA binding experiments showed that 1) the transcription factors STATE (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) bind to sites located around -110 and -650, respectively; and 2) STATE binding is induced and HNF-4 binding affinity is increased in liver within 1 h after GH injection to hypophysectomized rats. Using transfection experiments and site-directed mutagenesis, we found that STATE and HNF-4 stimulated transcription of an hnf6 gene promoter-reporter construct. Furthermore, GH stimulated transcription of this construct in cells that express GH receptors. Consistent with our earlier finding that HNF-6 stimulates the hnf4 and hnf3 beta gene promoters, GH treatment of hypophysectomized rats increased the liver concentration of HNF-4 and HNF-3 beta mRNAs, Together, these data demonstrate that GH stimulates transcription of the hnf6 gene by a mechanism involving STATE and HNF-4. They show that HNF-6 participates not only as an effector, but also as a target, to the regulatory network of liver transcription factors, and that several members of this network are GH regulated.
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页码:285 / 294
页数:10
相关论文
共 30 条
[1]   Mechanism of signaling by growth hormone receptor [J].
Argetsinger, LS ;
CarterSu, C .
PHYSIOLOGICAL REVIEWS, 1996, 76 (04) :1089-1107
[2]  
Bailly A, 1998, J CELL SCI, V111, P2411
[3]   Cytokine receptor-independent, constitutively active variants of STAT5 [J].
Berchtold, S ;
Moriggl, R ;
Gouilleux, F ;
Silvennoinen, O ;
Beisenherz, C ;
Pfitzner, E ;
Wissler, M ;
Stocklin, E ;
Groner, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (48) :30237-30243
[4]   Liver-enriched transcription factors and hepatocyte differentiation [J].
Cereghini, S .
FASEB JOURNAL, 1996, 10 (02) :267-282
[5]   ISOLATION OF BIOLOGICALLY-ACTIVE RIBONUCLEIC-ACID FROM SOURCES ENRICHED IN RIBONUCLEASE [J].
CHIRGWIN, JM ;
PRZYBYLA, AE ;
MACDONALD, RJ ;
RUTTER, WJ .
BIOCHEMISTRY, 1979, 18 (24) :5294-5299
[6]  
Demoulin JB, 1996, MOL CELL BIOL, V16, P4710
[7]   Regulation of a transcription factor network required for differentiation and metabolism [J].
Duncan, SA ;
Navas, MA ;
Dufort, D ;
Rossant, J ;
Stoffel, M .
SCIENCE, 1998, 281 (5377) :692-695
[8]   Desensitization of the growth hormone-induced Janus kinase 2 (Jak 2) signal transducer and activator of transcription 5 (Stat5)-signaling pathway requires protein synthesis and phospholipase C [J].
Fernández, L ;
Flores-Morales, A ;
Lahuna, O ;
Sliva, D ;
Norstedt, G ;
Haldosén, LA ;
Mode, A ;
Gustafsson, JÅ .
ENDOCRINOLOGY, 1998, 139 (04) :1815-1824
[9]   A NOVEL IN-VITRO MODEL FOR STUDYING SIGNAL-TRANSDUCTION AND GENE-REGULATION VIA THE GROWTH-HORMONE RECEPTOR [J].
FRANCIS, SM ;
ENERBACK, S ;
MOLLER, C ;
ENBERG, B ;
NORSTEDT, G .
MOLECULAR ENDOCRINOLOGY, 1993, 7 (08) :972-978
[10]   DNA binding and transcription activation specificity of hepatocyte nuclear factor 4 [J].
Fraser, JD ;
Martinez, V ;
Straney, R ;
Briggs, MR .
NUCLEIC ACIDS RESEARCH, 1998, 26 (11) :2702-2707