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Sterol regulatory element-binding protein (SREBP)-1a is a unique mem-brane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol, fatty acids, and phospholip-ids. Because mammalian cells need to synthesize membrane lipids for cell replication, the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. | ễFEBS Journal A transcription factor of lipid synthesis sterol regulatory element-binding protein SREBP -la causes G1 cell-cycle arrest after accumulation of cyclin-dependent kinase cdk inhibitors Masanori Nakakuki1 Hitoshi Shimano1 2 Noriyuki Inoue1 Mariko Tamura1 Takashi Matsuzaka1 Yoshimi Nakagawa1 2 Naoya Yahagi2 Hideo Toyoshima1 Ryuichiro Sato3 and Nobuhiro Yamada1 1 Department of InternalMedicine Endocrinology and Metabolism Graduate Schoolof Comprehensive Human Sciences University of Tsukuba Japan 2 Center for Tsukuba Advanced Research Alliance University of Tsukuba Japan 3 Department of Applied BiologicalChemistry Graduate Schoolof Agriculturaland Life Sciences University of Tokyo Japan Keywords cell growth cholesterol fatty acids p21 p27 Correspondence H. Shimano 1-1-1Tennodai Tsukuba Ibaraki 305-8575 Japan Fax 81 29 853 3174 Tel 81 29 853 3053 E-mail shimano-tky@umin.ac.jp Received 9 November 2006 revised 25 June 2007 accepted 2 July 2007 doi 10.1111 j.1742-4658.2007.05973.x Sterol regulatory element-binding protein SREBP -la is a unique membrane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol fatty acids and phospholipids. Because mammalian cells need to synthesize membrane lipids for cell replication the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. However the effect of this potent lipid-synthesis activator on cell growth has never been explored. Here we show that induction of nuclear SREBP-1a but not SREBP-2 completely inhibited cell growth in inducible Chinese hamster ovary CHO cell lines. Growth inhibition occurred through G1 cell-cycle arrest which is observed in various cell types with transient expression of nuclear SREBP-1a. SREBP-1a caused the accumulation of cyclin-dependent kinase cdk inhibitors such as p27 p21 and p16 leading to reduced cdk2 and cdk4 activities and hypophosphorylation of Rb protein. In contrast to .
