The p53 tumor suppressor protein regulates hematopoietic stem cell fate

Abstract

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.

Fig 1. Multiple functions of p53 at physiological and stress conditions

p53 can induce a variety of cellular responses depending on the nature, level and duration of stress signals. When expressed at low level under physiological condition, p53 plays homeostatic roles such as anti-oxidant function and maintenance of stem cell functions. Increasing level of stress augments the level of p53 expression which induces apoptosis, thereby eliminate damaged cells.

Fig 2. Role of p53 in hematopoietic stem cells

(A) Under normal condition, p53 has been shown to regulate hematopoietic stem cell quiescence mediated by Gfi-1 and Necdin. It is likely to maintain self-renewal by yet unknown mechanism. (B) Increasing level of stress triggers ATM activation which will increase p53 activation. By downstream mediators such as p21, Puma and Slug, p53 triggers cell cycle arrest, DNA repair or apoptosis.