Loss of insulin-like growth factor I receptor-dependent expression of p107and cyclin A in cells that lack the extracellular matrix protein secreted protein acidic and rich in cysteine

The extracellular matrix-associated glycoprotein secreted protein acidic an d rich in cysteine (SPARC) has been implicated in the control of cell proli feration during tissue remodeling, wound healing, and malignant development . Here, we describe a novel mechanism through which SPARC influences cell c ycle progression in embryonic fibroblasts derived from Sparc-nullizygous (- /-) mice. SPARC-deficient cells were indistinguishable from wild-type cells in their ability to initiate DNA synthesis after treatment with either fet al bovine serum or platelet-derived growth factor. In contrast, Spare -/- c ells responded poorly to activation of the insulin-like growth factor recep tor (IGFI-R) by insulin. This defect was traced to reduced expression of th e IGFI-R in Spare: -/- cells. Consistent with impaired cell cycle progressi on through S-phase, insulin-stimulated Spare -/- cells also revealed reduce d expression of two key regulators of S phase progression (cyclin A and thy midine kinase), whereas expression of the G(1) phase progression regulators c-myc or cyclin D1 was unaffected. An examination of the status of retinob lastoma family pocket proteins in Spare -/- cells revealed a selective and dramatic reduction in levels of the retinoblastoma-related protein p107, Ex ogenous platelet-derived growth factor restored expression of the IGFI-R an d IGFI-R dependent DNA synthesis as well as induction of cyclin A, thymidin e kinase, and p107 in insulin-stimulated Spare -/- cells. These results sug gest that SPARC-dependent matrix to cell interactions contribute to the reg ulation of p107 and cyclin A through IGFI-R dependent pathway(s).