Growth Hormone Signaling to the Nucleus

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DESCRIPTION (provided by applicant): Growth hormone (GH) exerts profound physiological effects on growth and metabolism, and is implicated in insulin resistance and possibly cancer. Many responses to GH depend on its ability to regulate gene transcription. We hypothesize that GH-regulated transcription is mediated by the ordered assembly of multicomponent nucleoprotein complexes on target genes and that GH-induced modifications of critical proteins can direct them into and out of the complexes. Our approach is to dissect the assembly of the multicomponent complexes in response to GH using chromatin immunoprecipitation (ChIP) and re-ChIP to define GH-regulated components of complexes and determine the dynamics of assembly on the model gene c-fos. In parallel, we will also examine post-translational modifications induced by GH on the transcription factor C/EBPp, which is essential for GH-stimulated transcription of c-fos. The sequence of complex assembly will be related to the timing and combinations of post-translational modifications of C/EBPp including phosphorylation, acetylation and sumoylation. When regulation of complexes by GH is determined, we will validate their functional importance for GH-regulated gene expression in vivo. Relevance: GH is used for treatment of short stature in GH deficiency. The anabolic properties of GH are being used therapeutically to improve wound healing and to reverse wasting in HIV patients. However, GH is also diabetogenic and reduces sensitivity to insulin. Recently, the GH-IGF axis has been implicated in cancer, broadening our need to understand the basis of GH action. The proposed studies will provide fundamental information about how GH alters cell function by regulating genes. With this information, we can identify new molecular targets to develop more effective therapies for conditions responsive to GH and to avoid GH-related complications in conditions such as diabetes and cancer.