Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis.
Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis.
复制标题
检查点激酶1是正常B细胞发育和淋巴瘤发生所必需的。
DOI：
10.1038/s41467-017-01850-4
复制
发表时间：
2017-11-22
影响因子：
16.6
通讯作者：
Villunger A
中科院分区：
文献类型：
--
作者：
Schuler F;Weiss JG;Lindner SE;Lohmüller M;Herzog S;Spiegl SF;Menke P;Geley S;Labi V;Villunger A
检查点蛋白1(Checkpoint kinase1，CHK1)对细胞周期的内在调控和DNA损伤后细胞周期进程的协调起着关键作用。尽管CHK1具有基本功能，但它已被确定为杀死癌细胞的靶点，使用CHK1单倍体缺陷小鼠的研究最初表明它具有肿瘤抑制作用。在这里，我们报告CHK1在正常B细胞发育、淋巴肿大和细胞存活中的关键作用。化学CHK1抑制诱导BCL2调控的原发和恶性B细胞的凋亡，CHK1的表达水平控制小鼠淋巴肿大的发生时间。此外，完全切除B细胞中的Chk1会阻止它们在亲B细胞阶段的发育，令人惊讶的是，这一障碍不能通过抑制线粒体凋亡来克服，因为细胞周期停滞是作为限制受损DNA扩散的另一种命运启动的。我们的发现将CHK1定义为B细胞发育所必需的，也是治疗血癌的有效靶点。检查点蛋白1(Checkpoint kinase1，CHK1)对细胞周期的内在调控和细胞周期进程的协调至关重要。在这里，作者表明CHK1的缺失或化学抑制对正常的B细胞发育、淋巴肿大和癌细胞存活产生影响。
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression in response to DNA damage. Despite its essential function, CHK1 has been identified as a target to kill cancer cells and studies using Chk1 haploinsufficient mice initially suggested a role as tumor suppressor. Here, we report on the key role of CHK1 in normal B-cell development, lymphomagenesis and cell survival. Chemical CHK1 inhibition induces BCL2-regulated apoptosis in primary as well as malignant B-cells and CHK1 expression levels control the timing of lymphomagenesis in mice. Moreover, total ablation of Chk1 in B-cells arrests their development at the pro-B cell stage, a block that, surprisingly, cannot be overcome by inhibition of mitochondrial apoptosis, as cell cycle arrest is initiated as an alternative fate to limit the spread of damaged DNA. Our findings define CHK1 as essential in B-cell development and potent target to treat blood cancer. Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression. Here the authors show that CHK1 loss or chemical inhibition impacts on normal B cell development, lymphomagenesis and cancer cell survival.
登录
查看更多内容
影响因子：
64.5
作者：
Burgess RC;Misteli T
通讯作者：
Misteli T
影响因子：
8
作者：
Krystyniak, A;Garcia-Echeverria, C;Ferrari, S
通讯作者：
Ferrari, S
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
--
作者：
Derenzini, Enrico;Agostinelli, Claudio;Zinzani, Pier Luigi
通讯作者：
Zinzani, Pier Luigi
影响因子：
8
作者：
Fishler T;Li YY;Wang RH;Kim HS;Sengupta K;Vassilopoulos A;Lahusen T;Xu X;Lee MH;Liu Q;Elledge SJ;Ried T;Deng CX
通讯作者：
Deng CX