title: Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.
abstract: 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.
authors: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors: Yunyuan V
authors: YV
authors: Wang
authors: Mathias
authors: M
authors: Leblanc
authors: Norma
authors: N
authors: Fox
authors: Jian-Hua
authors: JH
authors: Mao
authors: Kelsey L
authors: KL
authors: Tinkum
authors: Kurt
authors: K
authors: Krummel
authors: Dannielle
authors: D
authors: Engle
authors: David
authors: D
authors: Piwnica-Worms
authors: Helen
authors: H
authors: Piwnica-Worms
authors: Allan
authors: A
authors: Balmain
authors: Kenneth
authors: K
authors: Kaushansky
authors: Geoffrey M
authors: GM
authors: Wahl
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D005720:Gamma Rays; D018628:Gene Dosage; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D006706:Homeostasis / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2