Raman Malavika, Earnest Svetlana, Zhang Kai, Zhao Yingming, Cobb Melanie H
Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390-9041, USA.
EMBO J. 2007 Apr 18;26(8):2005-14. doi: 10.1038/sj.emboj.7601668. Epub 2007 Mar 29.
Thousand and one amino acid (TAO) kinases are Ste20p-related MAP kinase kinase kinases (MAP3Ks) that activate p38 MAPK. Here we show that the TAO kinases mediate the activation of p38 in response to various genotoxic stimuli. TAO kinases are activated acutely by ionizing radiation, ultraviolet radiation, and hydroxyurea. Full-length and truncated fragments of dominant negative TAOs inhibit the activation of p38 by DNA damage. Inhibition of TAO expression by siRNA also decreases p38 activation by these agents. Cells in which TAO kinases have been knocked down are less capable of engaging the DNA damage-induced G2/M checkpoint and display increased sensitivity to IR. The DNA damage kinase ataxia telangiectasia mutated (ATM) phosphorylates TAOs in vitro; radiation induces phosphorylation of TAO on a consensus site for phosphorylation by the ATM protein kinase in cells; and TAO and p38 activation is compromised in cells from a patient with ataxia telangiectasia that lack ATM. These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM.
一千零一种氨基酸（TAO）激酶是与Ste20p相关的丝裂原活化蛋白激酶激酶激酶（MAP3K），可激活p38丝裂原活化蛋白激酶（p38 MAPK）。在此我们表明，TAO激酶介导p38对各种基因毒性刺激的激活反应。TAO激酶可被电离辐射、紫外线辐射和羟基脲迅速激活。显性负性TAO的全长和截短片段可抑制DNA损伤引起的p38激活。通过小干扰RNA（siRNA）抑制TAO表达也会降低这些试剂对p38的激活作用。TAO激酶被敲低的细胞参与DNA损伤诱导的G2/M期检查点的能力较弱，并对电离辐射表现出更高的敏感性。DNA损伤激酶共济失调毛细血管扩张症突变基因（ATM）在体外可使TAO磷酸化；辐射可诱导细胞中TAO在ATM蛋白激酶磷酸化的共有位点发生磷酸化；在缺乏ATM的共济失调毛细血管扩张症患者的细胞中，TAO和p38的激活受到损害。这些发现表明，TAO激酶是p38介导的对DNA损伤反应的调节因子，并且是ATM激活p38过程中的中间介质。
