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

Genes & development | Jul 1, 2011

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 RIS Download

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

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Associated grants

  • Agency: NCI NIH HHS, Id: CA094056
  • Agency: NCI NIH HHS, Id: P50 CA094056
  • Agency: NCI NIH HHS, Id: CA100845
  • Agency: NCI NIH HHS, Id: U01 CA84244
  • Agency: NCI NIH HHS, Id: R01 CA100845
  • Agency: NCI NIH HHS, Id: CA61449
  • Agency: NCI NIH HHS, Id: 5P30CA014195
  • Agency: NCI NIH HHS, Id: R01 CA061449
  • Agency: NCI NIH HHS, Id: U01 CA084244
  • Agency: NCI NIH HHS, Id: P30 CA014195

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