Beclin-1-p53 interaction is crucial for cell fate determination in embryonal carcinoma cells.
Beclin-1-p53 interaction is crucial for cell fate determination in embryonal carcinoma cells.
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DOI：
10.1111/jcmm.12386
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发表时间：
2014-11
影响因子：
5.3
通讯作者：
Shaha C
中科院分区：
文献类型：
--
作者：
Tripathi R;Ash D;Shaha C
在癌症化疗的背景下，人们对凋亡和自噬途径之间的相互关系产生了兴趣，这提供了令人兴奋的发现。来自两个途径的分子之间形成的复合体为化疗药物设计提供了潜在的靶点，因为破坏这种复合体可能会改变细胞的存活。本研究证实了Beclin-1和P53的相互作用在决定人胚胎癌细胞命运中的重要作用。这些发现为p53与Beclin-1通过Beclin-1的BH3结构域相互作用提供了证据。这种相互作用通过赖氨酸48连接促进了Beclin-1的泛素化，导致蛋白酶体介导的降解，从而维持了Beclin-1的一定组成水平。通过shRNA介导的p53下调来阻断Beclin-1-P53的相互作用，减少了Beclin-1的泛素化，这表明这一过程需要P53。因此，泛素化的减少导致Beclin-1水平的增加，细胞表现出高的自噬活性。在P53下调的细胞中强制过表达P53，恢复了Beclin-1的泛素化，降低了其水平，并降低了自噬活性。顺铂诱导的压力也破坏了Beclin-1-P53的相互作用，导致更高水平的Beclin-1，因为泛素化程度较低。这种较高浓度的Beclin-1增加了自噬，并为细胞免受顺铂诱导的死亡提供了保护。在体外和体内生长的异种移植瘤中，通过药物或遗传手段抑制自噬增加了体外和体内生长的异种移植瘤的凋亡死亡，证实了自噬的保护性。因此，Beclin-1-P53相互作用定义了一个额外的分子子程序，对胚胎癌细胞的细胞命运决定至关重要。
Emerging interest on the interrelationship between the apoptotic and autophagy pathways in the context of cancer chemotherapy is providing exciting discoveries. Complexes formed between molecules from both pathways present potential targets for chemotherapeutics design as disruption of such complexes could alter cell survival. This study demonstrates an important role of Beclin-1 and p53 interaction in cell fate decision of human embryonal carcinoma cells. The findings provide evidence for p53 interaction with Beclin-1 through the BH3 domain of the latter. This interaction facilitated Beclin-1 ubiquitination through lysine 48 linkage, resulting in proteasome-mediated degradation, consequently maintaining a certain constitutive level of Beclin-1. Disruption of Beclin-1–p53 interaction through shRNA-mediated down-regulation of p53 reduced Beclin-1 ubiquitination suggesting requirement of p53 for the process. Reduction of ubiquitination consequently resulted in an increase in Beclin-1 levels with cells showing high autophagic activity. Enforced overexpression of p53 in the p53 down-regulated cells restored ubiquitination of Beclin-1 reducing its level and lowering autophagic activity. The Beclin-1–p53 interaction was also disrupted by exposure to cisplatin-induced stress resulting in higher level of Beclin-1 because of lesser ubiquitination. This higher concentration of Beclin-1 increased autophagy and offered protection to the cells from cisplatin-induced death. Inhibition of autophagy by either pharmacological or genetic means during cisplatin exposure increased apoptotic death in vitro as well as in xenograft tumours grown in vivo confirming the protective nature of autophagy. Therefore, Beclin-1–p53 interaction defines one additional molecular subroutine crucial for cell fate decisions in embryonal carcinoma cells.
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Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平。
影响因子：
64.5
作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
通讯作者：
Yuan J
影响因子：
4.4
作者：
Prabhu, Varun;Srivastava, Pragya;Yadav, Neelu;Amadori, Michael;Schneider, Andrea;Seshadri, Athul;Pitarresi, Jason;Scott, Rachael;Zhang, Honghao;Koochekpour, Shahriar;Gogada, Raghu;Chandra, Dhyan
通讯作者：
Chandra, Dhyan
DOI：
10.1016/j.biocel.2013.02.007
发表时间：
2013-05-01
影响因子：
4
作者：
Fu, Lei-lei;Cheng, Yan;Liu, Bo
通讯作者：
Liu, Bo
影响因子：
3.7
作者：
Abada, Paolo B.;Howell, Stephen B.
通讯作者：
Howell, Stephen B.
影响因子：
--
作者：
Chu, Charleen T.;Plowey, Edward D.;Dagda, Ruben K.;Hickey, Robert W.;Cherra, Salvatore J., III;Clark, Robert S. B.
通讯作者：
Clark, Robert S. B.