TY - JOUR
T1 - The E3 ubiquitin ligase mule acts through the ATM-p53 axis to maintain b lymphocyte homeostasis
AU - Hao, Zhenyue
AU - Duncan, Gordon S.
AU - Su, Yu Wen
AU - Li, Wanda Y.
AU - Silvester, Jennifer
AU - Hong, Claire
AU - You, Han
AU - Brenner, Dirk
AU - Gorrini, Chiara
AU - Haight, Jillian
AU - Wakeham, Andrew
AU - You-Ten, Annick
AU - McCracken, Susan
AU - Elia, Andrew
AU - Li, Qinxi
AU - Detmar, Jacqui
AU - Jurisicova, Andrea
AU - Hobeika, Elias
AU - Reth, Michael
AU - Sheng, Yi
AU - Lang, Philipp A.
AU - Ohashi, Pamela S.
AU - Zhong, Qing
AU - Wang, Xiaodong
AU - Mak, Tak W.
PY - 2012/1
Y1 - 2012/1
N2 - 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 Muledeficient 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.
AB - 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 Muledeficient 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.
UR - http://www.scopus.com/inward/record.url?scp=84863116292&partnerID=8YFLogxK
U2 - 10.1084/jem.20111363
DO - 10.1084/jem.20111363
M3 - Article
C2 - 22213803
AN - SCOPUS:84863116292
SN - 0022-1007
VL - 209
SP - 173
EP - 186
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -