P57 Kip2 and p27 Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70

Peng Zou, Hiroki Yoshihara, Kentaro Hosokawa, Ikue Tai, Kaori Shinmyozu, Fujiko Tsukahara, Yoshiro Maru, Keiko Nakayama, Keiichi Nakayama, Toshio Suda

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)247-261
Number of pages15
JournalCell stem cell
Volume9
Issue number3
DOIs
Publication statusPublished - Sep 2 2011

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HSC70 Heat-Shock Proteins
Hematopoietic Stem Cells
Cell Cycle
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p57
Cell Nucleus Active Transport
Up-Regulation
Transplantation
Phosphorylation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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P57 Kip2 and p27 Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. / Zou, Peng; Yoshihara, Hiroki; Hosokawa, Kentaro; Tai, Ikue; Shinmyozu, Kaori; Tsukahara, Fujiko; Maru, Yoshiro; Nakayama, Keiko; Nakayama, Keiichi; Suda, Toshio.

In: Cell stem cell, Vol. 9, No. 3, 02.09.2011, p. 247-261.

Research output: Contribution to journalArticle

Zou, P, Yoshihara, H, Hosokawa, K, Tai, I, Shinmyozu, K, Tsukahara, F, Maru, Y, Nakayama, K, Nakayama, K & Suda, T 2011, 'P57 Kip2 and p27 Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70', Cell stem cell, vol. 9, no. 3, pp. 247-261. https://doi.org/10.1016/j.stem.2011.07.003
Zou, Peng ; Yoshihara, Hiroki ; Hosokawa, Kentaro ; Tai, Ikue ; Shinmyozu, Kaori ; Tsukahara, Fujiko ; Maru, Yoshiro ; Nakayama, Keiko ; Nakayama, Keiichi ; Suda, Toshio. / P57 Kip2 and p27 Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. In: Cell stem cell. 2011 ; Vol. 9, No. 3. pp. 247-261.
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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

AU - Suda, Toshio

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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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