Functional impact of cancer patient-associated Bcl-xL mutations.
Functional impact of cancer patient-associated Bcl-xL mutations.
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作者：
Zhang T;Na JH;Li S;Chen Z;Zhang G;Pang S;Daniyan AF;Li Y;Shi L;Du YN
Bcl‐xL是一种抗凋亡蛋白，经常在癌症中过表达，以促进肿瘤细胞的存活。然而，我们先前已经表明，Bcl‐xL促进迁移，侵袭和转移独立于其在线粒体中的抗凋亡功能。Bcl‐xL的促转移功能可能需要其易位到细胞核中。除了过度表达，在大规模癌症基因组学项目中还发现了患者相关的Bcl‐xL突变。了解这些突变的功能将指导精准医学的发展。在这里，我们选择了四种患者相关的Bcl‐xL突变，R132W，N136K，R165W和A201T，以研究它们对抗凋亡，迁移和核转位的影响。我们发现，所有四个突变蛋白都可以在细胞核和胞质中检测到。虽然所有四种突变都破坏了抗凋亡功能，但其中一种突变体N136K显着提高了促进细胞迁移的能力。这些数据表明开发新型Bcl‐xL抑制剂以消除Bcl‐xL在癌症中的抗凋亡和促转移功能的重要性。Bcl‐xL因其在癌症中的抗凋亡功能而闻名。在这项研究中，我们描述了四种癌症相关的Bcl‐xL突变，R132W，N136K，R165W和A201T，在抗凋亡，迁移和核转位中表现不同。N136K和R165W削弱了Bcl‐xL的抗凋亡功能，但仍促进细胞迁移。特别是，N136K显著提高了促进细胞迁移的能力。这些数据表明，开发超越经典Bcl‐xL抑制剂的新策略以消除癌症中的抗凋亡和转移功能的重要性。
Bcl‐xL, an antiapoptotic protein, is frequently overexpressed in cancer to promote survival of tumor cells. However, we have previously shown that Bcl‐xL promotes migration, invasion, and metastasis independent of its antiapoptotic function in mitochondria. The pro‐metastatic function of Bcl‐xL may require its translocation into the nucleus. Besides overexpression, patient‐associated mutations of Bcl‐xL have been identified in large‐scale cancer genomics projects. Understanding the functions of these mutations will guide the development of precision medicine. Here, we selected four patient‐associated Bcl‐xL mutations, R132W, N136K, R165W, and A201T, to investigate their impacts on antiapoptosis, migration, and nuclear translocation. We found that all four mutation proteins could be detected in both the nucleus and cytosol. Although all four mutations disrupted the antiapoptosis function, one of these mutants, N136K, significantly improved the ability to promote cell migration. These data suggest the importance of developing novel Bcl‐xL inhibitors to ablate both antiapoptotic and pro‐metastatic functions of Bcl‐xL in cancer. Bcl‐xL is well‐known for its antiapoptotic function in cancer. In this study, we described that four cancer‐associated Bcl‐xL mutations, R132W, N136K, R165W, and A201T, behaved differently in antiapoptosis, migration, and nuclear translocation. N136K and R165W impaired the antiapoptotic function of Bcl‐xL, but still promoted cell migration. In particular, N136K significantly improved the ability to promote cell migration. These data suggested the importance of developing new strategies beyond canonical Bcl‐xL inhibitors to ablate both antiapoptotic and metastatic functions in cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16.6
作者：
Choi S;Chen Z;Tang LH;Fang Y;Shin SJ;Panarelli NC;Chen YT;Li Y;Jiang X;Du YN
通讯作者：
Du YN
影响因子：
11.2
作者：
Jones, Rebecca;Ruas, Margarida;Peters, Gordon
通讯作者：
Peters, Gordon
影响因子：
2.9
作者：
Lorch, M;Mason, JM;Clarke, AR
通讯作者：
Clarke, AR
影响因子：
--
作者：
Keitel U;Scheel A;Thomale J;Halpape R;Kaulfuß S;Scheel C;Dobbelstein M
通讯作者：
Dobbelstein M