The p53 tumor suppressor protein regulates hematopoietic stem cell fate

Abstract

Summary The p53 tumor suppressor protein is a key transcription factor that regulates several signaling pathways involved in the cell’s response to stress. Through stress-induced activation, p53 accumulates and triggers the expression of target genes that protect the genetic integrity of all cells including hematopoietic stem cells (HSCs). These protective mechanisms include cell-cycle arrest, DNA repair, induction of apoptosis, or initiation of senescence. In addition to its function under stress conditions, p53 has important functions during steady-state hematopoiesis, regulating HSC quiescence and self-renewal. In addition, it appears that p53 levels affect HSC competition for the hematopoietic niche, with the less p53 activated HSCs preferentially surviving. The specific genes and precise mechanisms underlying p53’s effects on normal HSCs are slowly being clarified. p53 also plays an important role in leukemia stem cell (LSC) behavior, with p53 loss affecting drug resistance and disease progression. Pharmacologic activation of p53 function could overcome the adverse impact of p53 inactivation in LSCs. Thus, understanding the p53 regulatory mechanisms active in HSCs and LSCs may promote the development of new therapeutic strategies that could eliminate the population of largely quiescent LSCs.

Prdm16 is a physiologic regulator of hematopoietic stem cells

“…Consistent with this finding, expression of Trp53 (p53) and its prime target, Puma, 34 as well as Tmbim4, a potential Bax inhibitor, 38 was increased. Trp53 Ϫ/Ϫ mice have an expanded HSPC compartment, 34,35 whereas Puma Ϫ/Ϫ mice are resistant to hematopoietic failure caused by irradiation and cytotoxic drugs.…”

“…Maintenance of the HSC function in the long-term requires a critical balance between renewing and differentiating proliferation, quiescence, and survival, as well as appropriate homeostatic responses to damage and stress. 1,34 Both in mouse models where HSC quiescence is increased, such as Mef Ϫ/Ϫ and Bmi1 Ϫ/Ϫ mice, 31,49 and in models where HSC cell cycle activity is increased, such as Gfi Ϫ/Ϫ , Evi1 Ϫ/Ϫ , and Pbx1 Ϫ/Ϫ mice, 5,33,50 longterm HSC function is severely compromised. Prdm16 Ϫ/Ϫ NSCs have been reported to display increased oxidative stress and to express less hepatocyte growth factor (Hgf) mRNA.…”

“…Genes known to be involved in HSC function, renewal, and maintenance (Bmi1, Pbx1, Evi1, and Gata2), 5,[31][32][33] apoptosis (Trp53, Puma, and Tmbim4), [34][35][36][37][38] cell cycle regulation (Cdk4, Cdkn1a, Cdk1nb, and Ckdn1c), 39,40 as well as cytokines and genes involved in cytokine signaling (Notch1, Angpt1, Angpt2, Ryk, Wnt3a, and Smad2) [41][42][43][44][45] were selected. Prdm16 Ϫ/Ϫ neural stem cells (NSCs) have been reported to display increased oxidative stress.…”

“…46 The expression of the negative cell cycle regulators Cdkn1a and Cdk1nb was mildly higher in Prdm16 Ϫ/Ϫ than in wt HSCs. Expression of Trp53 (p53) and one of its prime transcriptional targets, Puma, 34 as well as that of the potential Bax inhibitor Tmbim4 was higher in Prdm16 Ϫ/Ϫ than in wt HSCs. These observations may explain the increased apoptosis observed in Prdm16 Ϫ/Ϫ HSCs.…”

Cell cycle regulation in hematopoietic stem cells

“…Interestingly, growth-repressive signals such as TGF- directly target the p21 Cip and p57 Kip2 genes, suggesting a role for the BM niche in regulating expression of these CKIs in HSCs (Scandura et al, 2004). Interestingly, p53, a master transcriptional regulator that induces the transcription of p21 CIP in addition to a plethora of other genes upon cellular insult, also regulates HSC quiescence (Asai et al, 2011). p53 / HSCs have increased BrdU incorporation and decreased frequency of G 0 cells .…”