The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis Academic Article uri icon

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  • Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell–specific Mule knockout (BMKO) mice were generated using the Cre–LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho–ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM–p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.


  • Hao, Zhenyue
  • Duncan, Gordon S
  • Su, Yu-Wen
  • Li, Wanda Y
  • Silvester, Jennifer
  • Hong, Claire
  • You, Han
  • Brenner, Dirk
  • Gorrini, Chiara
  • Haight, Jillian
  • Wakeham, Andrew
  • You-Ten, Annick
  • McCracken, Susan
  • Elia, Andrew
  • Li, Qinxi
  • Detmar, Jacqui
  • Jurisicova, Andrea
  • Hobeika, Elias
  • Reth, Michael
  • Sheng, Yi
  • Lang, Philipp A
  • Ohashi, Pamela S
  • Zhong, Qing
  • Wang, Xiaodong
  • Mak, Tak W

publication date

  • January 16, 2012

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