Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1

被引：36
作者：
Cai Bowen [1 ,2 ]
Ju, Jeong-Ho [1 ,2 ]
Lee, Ji-Hoon [3 ,4 ,5 ]
Paull, Tanya T. [3 ,4 ,5 ]
Gelmann, Edward P. [1 ,2 ]
机构：
[1] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Med, New York, NY 10032 USA
[2] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Pathol, New York, NY 10032 USA
[3] Univ Texas Austin, Howard Hughes Med Inst, Austin, TX 78712 USA
[4] Univ Texas Austin, Dept Mol Genet & Microbiol, Austin, TX 78712 USA
[5] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA
来源：
CELL REPORTS | 2013年 / 4卷 / 03期
关键词：
DNA-DAMAGE RESPONSE; BASE EXCISION-REPAIR; DOUBLE-STRAND BREAKS; TOPOISOMERASE-I; PROTEIN-KINASE; EXPRESSION; PHOSPHORYLATION; GENOME; GENE; AUTOPHOSPHORYLATION;
D O I：
10.1016/j.celrep.2013.06.039
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of gamma histone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a DNA-damage-independent manner. ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation. Thus, NKX3.1 and ATM have a functional interaction leading to ATM activation and then NKX3.1 degradation in a tightly regulated DNA damage response specific to prostate epithelial cells. These findings demonstrate a mechanism for the tumor-suppressor properties of NKX3.1, demonstrate how NKX3.1 may enhance DNA integrity in prostate stem cells and may help to explain how cells differ in their sensitivity to DNA damage.
引用
收藏
页码：516 / 529
页数：14
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