Journal
BIOCHEMICAL JOURNAL
Volume 397, Issue -, Pages 159-168Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20060332
Keywords
growth hormone (GH); hepatocyte nuclear factor 4 alpha (HNF4 alpha); Janus kinase 2 (JAK2); liver sexual dimorphism; signal transducer and activator of transcription 5b (STAT5b)
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Funding
- NIDDK NIH HHS [R01 DK033765, DK33765] Funding Source: Medline
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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4 alpha (hepatocyte nuclear factor 4 alpha), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4 alpha strongly inhibited beta-casein and ntcp (Na+/taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-gamma-stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4 alpha towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4a on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4 alpha, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4 alpha inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase I B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4 alpha blocked GH-stimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4 alpha exhibit bidirectional cross-talk that may augment HNF4 alpha-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4 alpha on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.
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