title: The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity.
abstract: The p53-Mdm2 feedback loop is perceived to be critical for regulating stress-induced p53 activity and levels. However, this has never been tested in vivo. Using a genetically engineered mouse with mutated p53 response elements in the Mdm2 P2 promoter, we show that feedback loop-deficient Mdm2(P2/P2) mice are viable and aphenotypic and age normally. p53 degradation kinetics after DNA damage in radiosensitive tissues remains similar to wild-type controls. Nonetheless, DNA damage response is elevated in Mdm2(P2/P2) mice. Enhanced p53-dependent apoptosis sensitizes hematopoietic stem cells (HSCs), causing drastic myeloablation and lethality. These results suggest that while basal Mdm2 levels are sufficient to regulate p53 in most tissues under homeostatic conditions, the p53-Mdm2 feedback loop is critical for regulating p53 activity and sustaining HSC function after DNA damage. Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies.
authors: Department of Genetics.
authors: Vinod
authors: V
authors: Pant
authors: Shunbin
authors: S
authors: Xiong
authors: James G
authors: JG
authors: Jackson
authors: Sean M
authors: SM
authors: Post
authors: Hussein A
authors: HA
authors: Abbas
authors: Alfonso
authors: A
authors: Quintás-Cardama
authors: Amirali N
authors: AN
authors: Hamir
authors: Guillermina
authors: G
authors: Lozano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D025461:Feedback, Physiological; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000528:radiation effects; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011489:Protein Denaturation / Q000528:radiation effects; D055550:Protein Stability / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: autoregulatory loop; bone marrow; hematopoietic stem cells; ionizing radiation; p53 stability
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