p57 Is Required for Quiescence and Maintenance of Adult Hematopoietic Stem Cells

Abstract

Quiescence is required for the maintenance of hematopoietic stem cells (HSCs). Members of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors (p21, p27, p57) have been implicated in HSC quiescence, but loss of p21 or p27 in mice affects HSC quiescence or functionality only under conditions of stress. Although p57 is the most abundant family member in quiescent HSCs, its role has remained uncharacterized. Here we show a severe defect in the self-renewal capacity of p57-deficient HSCs and a reduction of the proportion of the cells in G(0) phase. Additional ablation of p21 in a p57-null background resulted in a further decrease in the colony-forming activity of HSCs. Moreover, the HSC abnormalities of p57-deficient mice were corrected by knocking in the p27 gene at the p57 locus. Our results therefore suggest that, among Cip/Kip family CDK inhibitors, p57 plays a predominant role in the quiescence and maintenance of adult HSCs.

Cell cycle regulation in hematopoietic stem cells

“…In addition, the defective quiescence phenotype of p57 Kip2 -deficient HSCs is exacerbated by concomitant deletion of either p21 Cip or p27 Kip1 , and p27 Kip1 overexpression is able to compensate for the loss of p57 Kip2 (Matsumoto et al, 2011;Zou et al, 2011). Taken together, these studies reveal p57 Kip2 as a critical regulator of HSC quiescence in adult mice, and suggest some degree of functional redundancies among the CIP/KIP family of CKIs.…”

“…hematopoietic-specific deletion of p57 Kip2 in adult mice suggests that p57 Kip2 is in fact critical for maintaining HSC quiescence (Matsumoto et al, 2011). In addition, the defective quiescence phenotype of p57 Kip2 -deficient HSCs is exacerbated by concomitant deletion of either p21 Cip or p27 Kip1 , and p27 Kip1 overexpression is able to compensate for the loss of p57 Kip2 (Matsumoto et al, 2011;Zou et al, 2011).…”

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

“…Although the suppression of p57kip2 was most remarkable, this would not account for the enhanced self-renewal activity of Fbxl10 Tg HSCs because a previous report showed that p57kip2 was required for HSC quiescence and its deficiency abrogated the self-renewal capacity of HSCs in mice. 23 To identify the differentially regulated functional networks accounting for growth advantage of HSCs in Tg mice, we applied gene set enrichment analysis (GSEA) to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, a database that represents molecular interaction networks, including metabolic pathways, regulatory pathways, and molecular complexes. This analysis revealed that in nonleukemic Tg HSCs, several gene sets were significantly upregulated with "oxidative phosphorylation (OXPHOS)" being the highest ( Figure 4A; Table 2), whereas no gene sets were significantly downregulated, as compared with the control HSCs.…”

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

“…Together, our data reveal a transcriptional network between TGFβ, Smad4, Smad7, Gata2, and p57, important for the regulation of hematopoietic progenitor cell proliferation. 18 Figure legends …”

“…Furthermore, p57-deficient HSCs show a severely decreased self-renewal capacity and a reduced proportion of quiescent cells 18 , suggesting that TGFβ has a role in keeping HSCs in a quiescent state through a mechanism involving the transcriptional activation of p57.…”