The goal of this research is to elucidate the mechanism(s) by which human growth (hGH) induces differentiation to murine 3T3-F442A fibroblasts to terminally differentiated adipocytes. our working hypothesis is that adipose differentiation is a nultistep multihormone process in which each step is hormonally regulated by GH and other polypeptide hormones. In this hypothesis we suggest that GH primes cells for subsequent action by insulin and insulin-like growth factor-1. Our preliminary data suggest that signatures of the GH primed state are changes in cell morphology, altered patterns of cytoskeletal protein expression, macromolecular synthesis, anti-mitogenesis, and tyrosine specific protein phosphorylation. The exact sequence of hormonal regulatory steps will be elucidated by the isolation of cell variants with unique hormonal requirements, use of suspension culture and identification of specific hormonal responses. The mechanism of the biological responses of differentiation and growth will be sought by studies of transcription, protein synthesis, and protein phosphorylation. Particular attention will be directed to specific proteins which are regulated by specific hormones. Preliminary experiments suggest that growth hormone modulates phosphorylation of tyrosine in proteins with prominent responses in growth factor receptors. Particular attention will be directed to insulin, insulin like growth factor-1, epidermal growth factor, transforming growth factor-beta and platelet derived growth factor receptors. These studies should contribute to an understanding of the mechanism by which growth hormone and other hormones modulate differentiation and growth.
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