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J. Biol. Chem., Vol. 281, Issue 44, 33467-33476, November 3, 2006

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The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation^*

Takashi Nomiyama¹, Takafumi Nakamachi, Florence Gizard, Elizabeth B. Heywood, Karrie L. Jones, Naganari Ohkura, Ryuzo Kawamori^¶, Orla M. Conneely^||, and Dennis Bruemmer²

From the Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536, National Cancer Center Research Institute, Tumor Endocrinology Project, Tokyo 104-0045, Japan, the ^¶Department of Medicine, Metabolism, and Endocrinology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, and the ^||Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expression in vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor (PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5'-Deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMP-response element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNA-mediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.

Received for publication, April 10, 2006 , and in revised form, August 25, 2006.

^* This work was supported in part by National Institutes of Health Grant RO1 HL084611-01 (to D. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by a fellowship grant from the Manpei Suzuki Diabetes Foundation, Japan.

² To whom correspondence should be addressed: Wethington Health Sciences Bldg., Rm. 575, 900 South Limestone St., Lexington, KY 40536-0200. Tel.: 859-323-4933 (ext. 81418); Fax: 859-257-3646; E-mail: Dennis.Bruemmer{at}uky.edu.

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