title: Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1.
abstract: A transcriptional regulator, Hes1, plays crucial roles in the control of differentiation and proliferation of neuronal, endocrine, and T-lymphocyte progenitors during development. Mechanisms for the regulation of cell proliferation by Hes1, however, remain to be verified. In embryonic carcinoma cells, endogenous Hes1 expression was repressed by retinoic acid in concord with enhanced p27(Kip1) expression and cell cycle arrest. Conversely, conditional expression of a moderate but not maximal level of Hes1 in HeLa cells by a tetracycline-inducible system resulted in reduced p27(Kip1) expression, which was attributed to decreased basal transcript rather than enhanced proteasomal degradation, with concomitant increases in the growth rate and saturation density. Hes1 induction repressed the promoter activity of a 5' flanking basal enhancer region of p27(Kip1) gene in a manner dependent on Hes1 expression levels, and this was mediated by its binding to class C sites in the promoter region. Finally, hypoplastic fetal thymi, as well as livers and brains of Hes1-deficient mice, showed significantly increased p27(Kip1) transcripts compared with those of control littermates. These results have suggested that Hes1 directly contributes to the promotion of progenitor cell proliferation through transcriptional repression of a cyclin-dependent kinase inhibitor, p27(Kip1).
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Murata
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.forename: Norihito
authors.initials: N
authors.lastname: Hirai
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Shinozuka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hirata
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018398:Homeodomain Proteins; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014212:Tretinoin; D025521:Tumor Suppressor Proteins; C493961:Cdkn1b protein, mouse; C489734:Hes1 protein, mouse