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J Biol Chem. 2002 Feb 22;277(8):6582-9. Epub 2001 Dec 17.

Cytokine-induced down-regulation of zfm1/splicing factor-1 promotes smooth muscle cell proliferation.

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Department of Cardiovascular Physiology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.


One hallmark of inflammation is the proliferation of bystander cells such as vascular smooth muscle cells (SMC), a process governed by growth factors and cytokines. Whereas cytokine induction of gene products promoting inflammation and proliferation is well characterized, little is known about the concomitant down-regulation of potentially counter-regulatory gene products in these cells. By employing the suppression subtractive hybridization-PCR technique, RNA isolated from rat aortic SMC treated with the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) was subtracted from RNA of control cells. Eleven genes were identified, the expression of which fell by 44-77%. One, the transcriptional repressor splicing factor-1 or zfm1, was characterized further. Antisense oligonucleotide suppression of zfm1 protein synthesis mimicked the stimulatory effects of IL-1 beta and TNF alpha on SMC proliferation and expression of the chemokine MCP-1 and the vascular cell adhesion molecule-1. Moreover, in an in vivo mouse model of atherosclerosis, zfm1 abundance was decreased in proliferating arterial SMC. These findings suggest a role for zfm1 in controlling both proliferation and expression of pro-inflammatory gene products in SMC. Therefore, cytokine-induced down-regulation of zfm1 expression may contribute to the pathogenesis of hyperproliferative inflammatory diseases.

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