Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells

J Cell Biol. 2007 Feb 12;176(4):535-44. doi: 10.1083/jcb.200611058.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arteries / cytology
  • Arteries / metabolism*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclin D
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Cyclins / drug effects
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronan Receptors / pharmacology
  • Hyaluronic Acid / metabolism*
  • Hyaluronic Acid / pharmacology
  • Mesoderm / cytology
  • Mesoderm / drug effects
  • Mesoderm / metabolism*
  • Mice
  • Mice, Knockout
  • Mitogens / metabolism
  • Mitogens / pharmacology
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • S-Phase Kinase-Associated Proteins / genetics
  • S-Phase Kinase-Associated Proteins / metabolism


  • Cyclin D
  • Cyclins
  • Hyaluronan Receptors
  • Mitogens
  • RNA, Messenger
  • S-Phase Kinase-Associated Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Hyaluronic Acid