title: Loss of insulin-like growth factor I receptor-dependent expression of p107 and cyclin A in cells that lack the extracellular matrix protein secreted protein acidic and rich in cysteine.
abstract: The extracellular matrix-associated glycoprotein secreted protein acidic and rich in cysteine (SPARC) has been implicated in the control of cell proliferation during tissue remodeling, wound healing, and malignant development. Here, we describe a novel mechanism through which SPARC influences cell cycle 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 fetal bovine serum or platelet-derived growth factor. In contrast, Sparc -/- cells responded poorly to activation of the insulin-like growth factor receptor (IGFI-R) by insulin. This defect was traced to reduced expression of the IGFI-R in Sparc -/- cells. Consistent with impaired cell cycle progression through S-phase, insulin-stimulated Sparc -/- cells also revealed reduced expression of two key regulators of S phase progression (cyclin A and thymidine kinase), whereas expression of the G1 phase progression regulators cmyc or cyclin D1 was unaffected. An examination of the status of retinoblastoma family pocket proteins in Sparc -/- cells revealed a selective and dramatic reduction in levels of the retinoblastoma-related protein p107. Exogenous platelet-derived growth factor restored expression of the IGFI-R and IGFI-R dependent DNA synthesis as well as induction of cyclin A, thymidine kinase, and p107 in insulin-stimulated Sparc -/- cells. These results suggest that SPARC-dependent matrix to cell interactions contribute to the regulation of p107 and cyclin A through IGFI-R dependent pathway(s).
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: A
authors.initials: A
authors.lastname: Basu
authors.forename: U
authors.initials: U
authors.lastname: Rodeck
authors.forename: G C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: C C
authors.initials: CC
authors.lastname: Howe
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019925:Cyclin A / Q000235:genetics*; D003545:Cysteine; D005109:Extracellular Matrix / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D015676:Osteonectin / Q000235:genetics* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D050720:Retinoblastoma-Like Protein p107; D016196:S Phase / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D013937:Thymidine Kinase / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D019925:Cyclin A; D007004:Hypoglycemic Agents; D007328:Insulin; D009687:Nuclear Proteins; D015676:Osteonectin; D010982:Platelet-Derived Growth Factor; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D013937:Thymidine Kinase; D017526:Receptor, IGF Type 1; D003545:Cysteine