title: Convergence of physical and chemical signaling in the modulation of vascular smooth muscle cell cycle and proliferation by fibrillar collagen-regulated P66Shc.
abstract: Arterial smooth muscle cell (SMC) phenotype and proliferation is regulated by their surrounding collagens, which transform from fibrillar to monomeric type in atherogenesis, and platelet-derived growth factor (PDGF)-BB/interleukin (IL)-1β. This study aims at elucidating the mechanisms by which physical (monomeric vs. fibrillar collagens) and chemical (PDGF-BB/IL-1βvs. vehicle controls) stimuli modulate SMC cycle and proliferation. SMCs were cultured on monomeric vs. fibrillar type I collagens. In parallel experiments, SMCs on fibrillar collagen were co-stimulated with PDGF-BB/IL-1β. These physical and chemical factors induced common SMC cycle signaling events, including up-regulations of cyclin-dependent kinase-4/6 and cyclins A/D1, phosphorylation of retinoblastoma (Rb) and its dissociations with E2F2/3. The physical and chemical inductions of SMC cycle signaling and progression were oppositely regulated by phosphatidylinositol 3-kinase (PI3K)-mediated Akt and p38 mitogen-activated protein kinase (MAPK). Fibrillar collagen degraded p66Shc, whose Ser36-phosphorylation plays important roles in the modulation of SMC cycle. Monomeric collagen and PDGF-BB/IL-1β co-stimulation induced p66Shc expression and Ser36-phosphorylation through β(1) integrin and PDGF receptor-β, respectively. In conclusion, our results demonstrate that fibrillar collagen-regulated p66Shc converges the physical and chemical stimuli to modulate SMC cycle and proliferation through PI3K-mediated Akt and p38 MAPK and their opposite regulation in downstream common cell cycle signaling cascades.
authors: Division of Medical Engineering Research, National Health Research Institutes, Miaoli 350, Taiwan.
authors: Yi-Ting
authors: YT
authors: Yeh
authors: Chih-I
authors: CI
authors: Lee
authors: Seh Hong
authors: SH
authors: Lim
authors: Li-Jing
authors: LJ
authors: Chen
authors: Wei-Li
authors: WL
authors: Wang
authors: Yung-Jen
authors: YJ
authors: Chuang
authors: Jeng-Jiann
authors: JJ
authors: Chiu
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects; D050197:Atherosclerosis / Q000473:pathology; D000077214:Becaplermin; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D023903:Coronary Restenosis / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D024022:Fibrillar Collagens / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016213:Cyclins; D024022:Fibrillar Collagens; D007375:Interleukin-1; D020574:Proto-Oncogene Proteins c-sis; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000077214:Becaplermin; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases