Abstract
Hepatocyte growth factor (HGF) plays a crucial role in the differentiation of skeletal muscle cells, where a process in which the retinoblastoma protein (pRb) has been implicated. We addressed the role of pRb in HGFโmediated effects on the proliferation and differentiation of adult skeletal muscle myoblasts. HGF shifted pRb to its hyperphosphorylation forms and increased the transactivation of E2F1, a transcription factor required for S phase entry. A constitutively active pRb mutant blocked HGFโdependent pRb phosphorylation and transactivation of E2F1 and increased cell proliferation. Accordingly, this mutant reversed the inhibitory effects of HGF on the expression of the cyclinโdependent kinase (CDK) inhibitor p27 and myogenic differentiation markers. HGFโmediated pRb phosphorylation was reversed by ectopic expression of p27, but neither the myogenic regulatory factor, MEF2, nor the myogenic inhibitory protein Twist had that effect. These results suggest that in response to HGF signaling, there is a decrease in p27 expression that results in an accumulation of hyperphosphorylated Rb protein, and subsequent progression of myoblasts into the G~1~ phase of the cell cycle. J. Cell. Physiol. 191: 173โ182, 2002. ยฉ 2002 WileyโLiss, Inc.