Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 88-108-GHRH, GH & IGF Biology & Signaling
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-96
Benjamin D Varco-Merth*1 and Peter S Rotwein2
1Oregon Health and Science University, Portland, OR, 2Oregon Health & Science University, Portland, OR
Signal transducers and activators of transcription (STATs) comprise a conserved family of seven transcription factors that mediate many of the biological responses to cytokines and hormones.  Several STATs are able to be activated by GH (1, 3, 5a, and 5b), share protein sequence similarity, have overlapping tissue expression profiles and bind identical DNA sequences.  Remarkably, only STAT5b plays a critical role in promoting somatic growth by GH through direct regulation of IGF-I gene expression, as evidenced by GH insensitivity, reduced serum IGF-I levels and diminished longitudinal growth in both mice and humans deficient in this protein.  Here we have investigated the biochemical mechanisms mediating the apparent specificity of STAT5b in controlling IGF-I gene transcription in response to GH.  FLAG-tagged versions of human STAT1, STAT3, STAT5a, and STAT5b were co-expressed with the GH receptor in cultured cells incubated with or without GH [50 nM].  Both STAT5a and STAT5b underwent tyrosine phosphorylation at comparable levels after GH treatment and both bound DNA probes corresponding to conserved GH-response elements with similar affinities, as measured by in vitro gel-mobility shift assays.  Analyses of GH-activated gene transcription by promoter-reporter assays also revealed that the potency of human STAT5a and STAT5b was comparable at conserved STAT5b-binding enhancers derived from the rat Igf1 locus (R2-4, R13-13.5, R34-5, R53-4, R57-9, R60-1).  Under the same experimental conditions, STAT1 and STAT3 were minimally stimulated by GH treatment, but STAT1 could be activated by exposure of cells to interferon gamma and STAT3 by a constitutively active GHR-Jak2 fusion protein.  Taken together, these results suggest that STAT5a could mediate many of the effects attributed to STAT5b in response to GH, and thus, under appropriate circumstances, should be able to compensate for loss of STAT5b in IGF-I gene regulation.  In contrast, the roles of STAT1 and STAT3 in GH action may be more specialized and their biochemical mechanisms of activation and action in response to GH require more study.

Nothing to Disclose: BDV, PSR

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