Absence of Wip1 partially rescues Atm deficiency phenotypes in mice.
Absence of Wip1 partially rescues Atm deficiency phenotypes in mice.
复制标题
DOI：
10.1038/onc.2011.303
复制
发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Donehower, L. A.
中科院分区：
文献类型：
--
作者：
Darlington, Y.;Nguyen, T-A;Moon, S-H;Herron, A.;Rao, P.;Zhu, C.;Lu, X.;Donehower, L. A.
野生型p53诱导磷酸酶1（WIP 1）是一种丝氨酸/苏氨酸磷酸酶，其使共济失调毛细血管扩张症突变（ATM）启动的DNA损伤反应途径中的蛋白质去磷酸化。WIP 1可能在ATM信号传导中发挥稳态作用，使细胞在DNA修复完成后恢复到正常的预应力状态。为了更好地理解WIP 1对ATM信号传导的影响，我们将ATM缺陷小鼠与Wip 1缺陷小鼠杂交，并表征双敲除后代的表型。我们假设Wip 1的缺失可能会挽救Atm缺陷表型。Atm基因敲除小鼠，像患有遗传性共济失调毛细血管扩张综合征的ATM缺陷型人类一样，表现出辐射敏感性、生育缺陷，并且易于发生T细胞淋巴瘤。大多数双基因敲除小鼠在很大程度上免受淋巴瘤发展的影响，并且与Atm缺失小鼠相比具有大大延长的寿命。双敲除小鼠的p53和H2 AX磷酸化和p21表达增加相比，他们的Atm空对应，表明增强p53和DNA损伤反应。此外，与Atm缺失小鼠相比，双敲除脾细胞显示出降低的染色体不稳定性。最后，双无效小鼠从Atm无效小鼠中观察到的不育缺陷中部分获救。这些结果表明，抑制WIP 1可能代表了一种有用的策略，用于一般癌症治疗，特别是A-T患者。
Wildtype p53-Induced Phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may play a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared to Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared to their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared to Atm null mice. Finally, doubly null mice were partially rescued from infertility defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
23.9
作者：
Demidov, Oleg N.;Timofeev, Oleg;Bulavin, Dmitry V.
通讯作者：
Bulavin, Dmitry V.
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A