Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.

Journal Article

Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.

Full Text

Duke Authors

Cited Authors

  • Wang, YV; Leblanc, M; Fox, N; Mao, J-H; Tinkum, KL; Krummel, K; Engle, D; Piwnica-Worms, D; Piwnica-Worms, H; Balmain, A; Kaushansky, K; Wahl, GM

Published Date

  • July 2011

Published In

Volume / Issue

  • 25 / 13

Start / End Page

  • 1426 - 1438

PubMed ID

  • 21724834

Pubmed Central ID

  • 21724834

Electronic International Standard Serial Number (EISSN)

  • 1549-5477

International Standard Serial Number (ISSN)

  • 0890-9369

Digital Object Identifier (DOI)

  • 10.1101/gad.2024411

Language

  • eng