ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
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DOI：
10.1038/emboj.2009.294
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发表时间：
2009-12-16
期刊：
影响因子：
11.4
通讯作者：
Chen, Jiandong
中科院分区：
文献类型：
--
作者：
Cheng, Qian;Chen, Lihong;Chen, Jiandong
电离辐射引起的p53的快速激活是ATM激酶介导的经典DNA损伤反应。然而，导致p53稳定的主要信号传导靶点和机制尚不清楚。我们在这份报告中表明，ATM诱导p53积累的泛素E3连接酶MDM 2磷酸化。MDM 2 RING结构域附近的多个ATM靶位点以冗余方式发挥作用，以提供稳健的DNA损伤信号传导。在没有DNA损伤的情况下，MDM 2 RING结构域形成介导p53多聚泛素化和蛋白酶体降解的寡聚体。ATM磷酸化抑制RING结构域寡聚化，特异性抑制p53聚泛素化。通过丙氨酸取代所有六个磷酸化位点来阻断MDM 2磷酸化会导致DNA损伤后p53的组成性降解。这些观察结果表明，ATM通过调节MDM 2 RING结构域寡聚化和E3连接酶持续合成能力来控制p53稳定性。促进或破坏E3寡聚化可能是信号传导激酶调节泛素化反应的一般机制，也是治疗干预的潜在靶点。The EMBO Journal（2009）28，3857-3867. doi：10.1038/doj.2009.294; 2009年10月8日在线发布
Rapid activation of p53 by ionizing irradiation is a classic DNA damage response mediated by the ATM kinase. However, the major signalling target and mechanism that lead to p53 stabilization are unknown. We show in this report that ATM induces p53 accumulation by phosphorylating the ubiquitin E3 ligase MDM2. Multiple ATM target sites near the MDM2 RING domain function in a redundant manner to provide robust DNA damage signalling. In the absence of DNA damage, the MDM2 RING domain forms oligomers that mediate p53 poly ubiquitination and proteasomal degradation. Phosphorylation by ATM inhibits RING domain oligomerization, specifically suppressing p53 poly ubiquitination. Blocking MDM2 phosphorylation by alanine substitution of all six phosphorylation sites results in constitutive degradation of p53 after DNA damage. These observations show that ATM controls p53 stability by regulating MDM2 RING domain oligomerization and E3 ligase processivity. Promoting or disrupting E3 oligomerization may be a general mechanism by which signalling kinases regulate ubiquitination reactions, and a potential target for therapeutic intervention. The EMBO Journal (2009) 28, 3857-3867. doi: 10.1038/emboj.2009.294; Published online 8 October 2009