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

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.

Pubmed ID: 21724834

Authors

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

Journal

Genes & development

Publication Data

July 1, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: 5P30CA014195
  • Agency: NCI NIH HHS, Id: CA094056
  • Agency: NCI NIH HHS, Id: CA100845
  • Agency: NCI NIH HHS, Id: CA61449
  • Agency: NCI NIH HHS, Id: U01 CA84244

Mesh Terms

  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Female
  • Gamma Rays
  • Gene Dosage
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Hematopoietic Stem Cells
  • Homeostasis
  • Longevity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Proto-Oncogene Proteins c-mdm2
  • Radiation Tolerance
  • Tumor Suppressor Protein p53