Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.
Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.
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DOI：
10.1083/jcb.200611058
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发表时间：
2007-02-12
期刊：
影响因子：
--
通讯作者：
Assoian RK
中科院分区：
文献类型：
--
作者：
Kothapalli D;Zhao L;Hawthorne EA;Cheng Y;Lee E;Puré E;Assoian RK
高相对分子质量(HMW)透明质酸(HA)广泛存在于细胞外基质中，但其生物学活性尚不完全清楚。我们以前曾报道，HMW-HA与CD44a结合可拮抗血管平滑肌细胞(SMC；Cuff，C.A.，D.Kothapalli，I.Azonobi，S.Chun，Y.Zhang，R.Belkin，C.Yeh，A.Secreto，R.K.Assoian，D.J.Rader和E.puré)由有丝分裂原诱导的S时相进入。2001年。J·克莱恩。投资。108：1031-1040)；我们现在描述潜在的分子机制，并记录其在体内的相关性。HMW-HA抑制有丝分裂原依赖的血管平滑肌细胞周期蛋白D1的诱导和p27kip1的下调。HMW-HA对p27kip1信使RNA水平无影响，但降低了SCF复合体中降解p27kip1的限速组分Skp2的表达。抢救实验确定细胞周期蛋白D1是HMW-HA的主要靶点。在成纤维细胞中也观察到了类似的结果，而在CD44缺失的细胞中没有检测到这些抗分裂作用。对野生型和CD44缺失小鼠动脉的分析表明，HMW-HA/CD44对Cyclin D1和Skp2基因表达的影响在体内被检测到，并与血管损伤后SMC增殖的变化有关。
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.
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