Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation

Publication date: Available online 4 January 2018 Source:Stem Cell Reports Author(s): Xiaoli Li, Andrew F. Wilson, Wei Du, Qishen Pang Overactive p53 has been proposed as an important pathophysiological factor for bone marrow failure syndromes, including Fanconi anemia (FA). Here, we report a p53-dependent effect on hematopoietic stem and progenitor cell (HSPC) proliferation in mice deficient for the FA gene Fanca. Deletion of p53 in Fanca −/− mice leads to replicative exhaustion of the hematopoietic stem cell (HSC) in transplant recipients. Using Fanca −/− HSCs expressing the separation-of-function mutant p53 515C transgene, which selectively impairs the p53 function in apoptosis but keeps its cell-cycle checkpoint activities intact, we show that the p53 cell-cycle function is specifically required for the regulation of Fanca −/− HSC proliferation. Our results demonstrate that p53 plays a compensatory role in preventing FA HSCs from replicative exhaustion and suggest a cautious approach to manipulating p53 signaling as a therapeutic utility in FA. Teaser In this article, Pang and colleagues demonstrate a p53-dependent HSPC proliferation regulation in mice deficient for the Fanca gene in the Fanconi anemia (FA) pathway. They show that the p53 cell-cycle function is specifically required for the regulation of FA HSC proliferation. These results suggest that overactive p53 may represent a compensatory checkpoint mechanism for FA HSC proliferation.

Source: Stem Cell Reports - January 4, 2018 Category: Stem Cells Source Type: research