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Published online February 12, 2007
doi:10.1083/jcb.200611058
The Journal of Cell Biology, Vol. 176, No. 4, 535-544
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Kothapalli et al.
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Article

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



Devashish Kothapalli1, Liang Zhao3, Elizabeth A. Hawthorne1, Yan Cheng1,2, Eric Lee3, Ellen Puré1,2,3,4, and Richard K. Assoian1,2,3

1 Department of Pharmacology and 2 Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Wistar Institute, Philadelphia, PA 19104
4 Ludwig Institute for Cancer Research, New York, NY 10158

Correspondence to Richard K. Assoian: rka{at}pharm.med.upenn.edu

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 p27kip1 in vascular SMCs. p27kip1 messenger RNA levels were unaffected by HMW-HA, but the expression of Skp2, the rate-limiting component of the SCF complex that degrades p27kip1, 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.

Abbreviations used in this paper: cdk, cyclin-dependent kinase; HA, hyaluronan; HMW, high molecular weight; MEF, mouse embryonic fibroblast; QPCR, quantitative PCR; SMC, smooth muscle cell.


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