title: Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.
abstract: High molecular weight (HMW) hyaluronan (HA) is widely distributed in the extracellular matrix, but its biological activities remain incompletely understood. We previously reported that HMW-HA binding to CD44 antagonizes mitogen-induced S-phase entry in vascular smooth muscle cells (SMCs; Cuff, C.A., D. Kothapalli, I. Azonobi, S. Chun, Y. Zhang, R. Belkin, C. Yeh, A. Secreto, R.K. Assoian, D.J. Rader, and E. Puré. 2001. J. Clin. Invest. 108:1031-1040); we now characterize the underlying molecular mechanism and document its relevance in vivo. HMW-HA inhibits the mitogen-dependent induction of cyclin D1 and down-regulation of p27(kip1) in vascular SMCs. p27(kip1) messenger RNA levels were unaffected by HMW-HA, but the expression of Skp2, the rate-limiting component of the SCF complex that degrades p27(kip1), was reduced. Rescue experiments identified cyclin D1 as the primary target of HMW-HA. Similar results were observed in fibroblasts, and these antimitogenic effects were not detected in CD44-null cells. Analysis of arteries from wild-type and CD44-null mice showed that the effects of HMW-HA/CD44 on cyclin D1 and Skp2 gene expression are detected in vivo and are associated with altered SMC proliferation after vascular injury.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Devashish
authors.initials: D
authors.lastname: Kothapalli
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hawthorne
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Eric
authors.initials: E
authors.lastname: Lee
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D056741:Cyclin D; D016213:Cyclins; D018960:Hyaluronan Receptors; D008934:Mitogens; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006820:Hyaluronic Acid