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Signalling cross-talk between hepatocyte nuclear factor 4alpha and growth-hormone-activated STAT5b.

ABSTRACT: In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4alpha (hepatocyte nuclear factor 4alpha), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4alpha 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 HNF4alpha towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4alpha 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 HNF4alpha, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4alpha inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4alpha blocked GH-stimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4alpha exhibit bi-directional cross-talk that may augment HNF4alpha-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4alpha on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

SUBMITTER: Park SH

PROVIDER: S-EPMC1479742 | biostudies-other | 2006 Jul

REPOSITORIES: biostudies-other

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| S-EPMC1482807 | biostudies-literature

Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon.

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| S-EPMC3581272 | biostudies-literature

Hepatocyte nuclear factor-4alpha is a central transactivator of the mouse Ntcp gene.

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| S-EPMC2519858 | biostudies-literature

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