title: p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70.
abstract: Cell cycle regulators play critical roles in the balance between hematopoietic stem cell (HSC) dormancy and proliferation. In this study, we report that cell cycle entry proceeded normally in HSCs null for cyclin-dependent kinase (CDK) inhibitor p57 due to compensatory upregulation of p27. HSCs null for both p57 and p27, however, were more proliferative and had reduced capacity to engraft in transplantation. We found that heat shock cognate protein 70 (Hsc70) interacts with both p57 and p27 and that the subcellular localization of Hsc70 was critical to maintain HSC cell cycle kinetics. Combined deficiency of p57 and p27 in HSCs resulted in nuclear import of an Hsc70/cyclin D1 complex, concomitant with Rb phosphorylation, and elicited severe defects in maintaining HSC quiescence. Taken together, these data suggest that regulation of cytoplasmic localization of Hsc70/cyclin D1 complex by p57 and p27 is a key intracellular mechanism in controlling HSC dormancy.
authors: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. zoupeng@sc.itc.heio.ac.jp
authors: Peng
authors: P
authors: Zou
authors: Hiroki
authors: H
authors: Yoshihara
authors: Kentaro
authors: K
authors: Hosokawa
authors: Ikue
authors: I
authors: Tai
authors: Kaori
authors: K
authors: Shinmyozu
authors: Fujiko
authors: F
authors: Tsukahara
authors: Yoshiro
authors: Y
authors: Maru
authors: Keiko
authors: K
authors: Nakayama
authors: Keiichi I
authors: KI
authors: Nakayama
authors: Toshio
authors: T
authors: Suda
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D050761:Cyclin-Dependent Kinase Inhibitor p57; D050883:HSC70 Heat-Shock Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27