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HORMONES AND SIGNALING

IGF-I stimulates human intestinal smooth muscle cell growth by regulation of G₁ phase cell cycle proteins

Departments of Medicine and Physiology, Medical College of Virginia Campus, Virginia Commonwealth University

Submitted 16 September 2003 ; accepted in final form 27 September 2003

Autocrine production of insulinlike growth factor-I (IGF-I) regulates growth of human intestinal muscle cells by activation of distinct phosphatidylinositol 3-kinase (PI3-kinase)-dependent and ERK1/2-dependent pathways. The aim of the present study was to determine the mechanisms by which IGF-I regulates the G₁ phase of the cell cycle and muscle cell proliferation. Incubation of quiescent cells with IGF-I stimulated time-dependent cell cycle progression measured by using fluorescence-activated cell sorting analysis and by incorporation of [³H]thymidine. Studies using a microarray-based approach were used initially to identify genes expressed in human intestinal muscle encoding proteins known to participate in the G₁ phase of the cell cycle that were regulated by IGF-I. Incubation of muscle cells for 24 h with IGF-I elicited greater than fivefold increase in the expression of cyclin D1 and greater than twofold increase in retinoblastoma protein (Rb1). IGF-I elicited a time-dependent increase in cyclin D1 protein levels mediated jointly by ERK1/2-dependent and PI3-kinase-dependent mechanisms. Increase in cyclin D1 levels was accompanied by a time-dependent increase in cyclin D1-dependent cyclin-dependent kinase-4 (CDK4) activity. IGF-I also elicited a rapid time-dependent increase in Rb-(Ser807/811) phosphorylation, the specific target of the cyclin D₁-dependent CDK4 kinase, and a slower increase in total Rb protein levels. We conclude that IGF-I stimulates G₁ phase progression, DNA synthesis, and cell proliferation of human intestinal smooth muscle cells. Effects of IGF-I on proliferation are mediated jointly by ERK1/2-dependent and PI3-kinase-dependent pathways that regulate cyclin D1 levels, CDK4 activity, and Rb activity.

retinoblastoma; cyclin D; cyclin-dependent kinase; extracellular signal-regulated kinase 1/2; phosphatidylinositol 3-kinase

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