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Molecular and Cellular Biology, October 2005, p. 8938-8947, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.8938-8947.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lipid Synthetic Transcription Factor SREBP-1a Activates p21WAF1/CIP1, a Universal Cyclin-Dependent Kinase Inhibitor

Noriyuki Inoue,1 Hitoshi Shimano,1* Masanori Nakakuki,1 Takashi Matsuzaka,1 Yoshimi Nakagawa,2 Takashi Yamamoto,1 Ryuichiro Sato,3 Akimitsu Takahashi,1 Hirohito Sone,1 Naoya Yahagi,2 Hiroaki Suzuki,1 Hideo Toyoshima,1 and Nobuhiro Yamada1

Department of Internal Medicine, Institute of Clinical Medicine,1 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan,2 Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan3

Received 30 March 2005/ Returned for modification 3 May 2005/ Accepted 1 July 2005

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids, triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind directly to a novel SREBP binding site in the promoter of the p21WAF1/CIP1 gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform consistently causes induction of p21 at both the mRNA and protein levels. Colony formation assays and polyploidy of livers from transgenic mice suggest that activation of p21 by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1 null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target might implicate a new paradigm in the link between lipid synthesis and cell growth.

* Corresponding author. Mailing address: Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Phone: 81298533053. Fax: 81298533053. E-mail: shimano-tky{at}umin.ac.jp.

Molecular and Cellular Biology, October 2005, p. 8938-8947, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.8938-8947.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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