A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G(1) cell-cycle arrest after accumulation of cyclin-dependent kinase (cdk) inhibitors.
Sterol regulatory element-binding protein (SREBP)-1a 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 G(1) 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 transactivation of p21, SREBP-1a activated p27 by enhancing stabilization of the protein through inhibition of SKP2 and KPC1. In vivo, SREBP-1a-expressing livers of transgenic mice exhibited impaired regeneration after partial hepatectomy. SREBP-1-null mouse embryonic fibroblasts had a higher cell proliferation rate than wild-type cells. The unexpected cell growth-inhibitory role of SREBP-1a provides a new paradigm to link lipid synthesis and cell growth.
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan.
Masanori
M
Nakakuki
Hitoshi
H
Shimano
Noriyuki
N
Inoue
Mariko
M
Tamura
Takashi
T
Matsuzaka
Yoshimi
Y
Nakagawa
Naoya
N
Yahagi
Hideo
H
Toyoshima
Ryuichiro
R
Sato
Nobuhiro
N
Yamada
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008055:Lipids / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000502:physiology*
D008055:Lipids; D047428:Protein Kinase Inhibitors; D051780:Sterol Regulatory Element Binding Protein 1; D018844:Cyclin-Dependent Kinases