Roles of p53 in various biological aspects of hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs) have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of "cell integrity" under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

Figure 1

Functions of p53 in response to DNA damage. Genomic stresses caused by ionizing radiation (IR), chemotherapy, and reactive oxygen species (ROS) activate DNA damage check point pathway, which leads to the activation of ATM and CHK2 and subsequent stabilization of p53. Then, stabilized p53 induces cell cycle arrest and DNA repair when DNA damage is moderate, whereas it activates apoptosis pathway when DNA damage is extensive.

Figure 2

Regulation of quiescence and self-renewal in HSCs by p53. Maintenance of quiescence in HSCs needs proper expression of p53. Decrease in p53 expression promotes self-renewal and differentiation of HSCs.

Figure 3

Possible mechanisms of HSC transdifferentiation. HSCs might directly transdifferentiate into another cell type (lower arrow) or through transient reprogramming in certain conditions. Loss of p53 might promote transient reprogramming for HSC transdifferentiation.

Figure 4

Schematic diagram of p53 roles in HSCs. p53 is involved in the control of response to DNA damage, self-renewal, quiescence, apoptosis, senescence, leukemogenesis, and plasticity in HSCs. Lines with an arrowhead indicate promotion and lines with a bar inhibition in steady state (black) or stress conditions (red).