title: Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors.
abstract: Interactions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity.
authors.affiliation: Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104, USA.
authors.forename: Kouros
authors.initials: K
authors.lastname: Motamed
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Funk
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.forename: Russell
authors.initials: R
authors.lastname: Ross
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
authors.forename: E Helene
authors.initials: EH
authors.lastname: Sage
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D015676:Osteonectin / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004791:Enzyme Inhibitors; D015676:Osteonectin; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases