TY - JOUR
T1 - P57 Kip2 and p27 Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70
AU - Zou, Peng
AU - Yoshihara, Hiroki
AU - Hosokawa, Kentaro
AU - Tai, Ikue
AU - Shinmyozu, Kaori
AU - Tsukahara, Fujiko
AU - Maru, Yoshiro
AU - Nakayama, Keiko
AU - Nakayama, Keiichi I.
AU - Suda, Toshio
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Cancer Stem Cells” from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, the Global COE program “Education and Research Center for Stem Cell Medicine” of Keio University, and a Grant-in-Aid for Japan Society for the Promotion of Science Fellows.
PY - 2011/9/2
Y1 - 2011/9/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stem.2011.07.003
DO - 10.1016/j.stem.2011.07.003
M3 - Article
C2 - 21885020
AN - SCOPUS:80052281899
SN - 1934-5909
VL - 9
SP - 247
EP - 261
JO - Cell stem cell
JF - Cell stem cell
IS - 3
ER -