p57Kip2 and p27Kip1 Cooperate to Maintain Hematopoietic Stem Cell Quiescence through Interactions with Hsc70

SummaryCell 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (238 K)Download as PowerPoint slideHighlights► Deletion of p57 in embryonic HSCs does not affect cell cycle progression ► Deletion of both p57 and p27 results in failure to maintain quiescence in HSCs ► Heat shock cognate protein 70 (Hsc70) interacts with both p57 and p27 ► The cytoplasmic localization of Hsc70 is critical in maintaining HSC quiescence