Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.
Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.
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DOI：
10.1038/ncb3378
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发表时间：
2016-07
影响因子：
21.3
通讯作者：
Gorgoulis VG
中科院分区：
文献类型：
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作者：
Galanos P;Vougas K;Walter D;Polyzos A;Maya-Mendoza A;Haagensen EJ;Kokkalis A;Roumelioti FM;Gagos S;Tzetis M;Canovas B;Igea A;Ahuja AK;Zellweger R;Havaki S;Kanavakis E;Kletsas D;Roninson IB;Garbis SD;Lopes M;Nebreda A;Thanos D;Blow JJ;Townsend P;Sørensen CS;Bartek J;Gorgoulis VG
细胞周期蛋白依赖性激酶抑制剂p21 WAF 1/Cip 1是肿瘤抑制蛋白p53的原型下游效应物。然而，来自人类癌症和小鼠模型的证据表明，p21 WAF 1/Cip 1在某些条件下可以发挥致癌活性。这种行为背后的机制仍然不清楚。在这种情况下，我们意外地注意到，主要在p53突变的人类癌症中，一个高度非典型的癌细胞亚群强烈表达p21 WAF 1/Cip 1也表现出增殖的迹象。这一发现表明，要么是对高水平p21 WAF 1/Cip 1的耐受性，要么是p21 WAF 1/Cip 1本身引导了一个选择性过程，导致了更具攻击性的后代。为了解决后一种情况，我们采用了p21 WAF 1/Cip 1诱导的p53无效细胞模型，并使用高通量筛选手段在较长的时间段内监测它们。在主要由于衰老而以生长停滞为特征的初始阶段之后，出现了p21 WAF 1/Cip 1细胞的亚群，表明增加的基因组不稳定性、侵袭性和化学抗性。在机制水平上，未缓解的p21 WAF 1/Cip 1产生使CRL 4CDT 2和SCFSkp 2泛素连接酶复合物“饱和”，从而减少复制许可机制的周转。复制许可的放松管制引发了复制压力，加剧了基因组的不稳定性。从概念上讲，当设计抗肿瘤策略时应考虑上述概念，因为p21 WAF 1/Cip 1也对p53非依赖性信号（包括各种化疗化合物）作出响应。
The cyclin-dependent kinase inhibitor p21WAF1/Cip1 is the prototype downstream effector of the tumor suppressor protein p53. Yet, evidence from human cancer and mice models, imply that p21WAF1/Cip1, under certain conditions, can exercise oncogenic activity. The mechanism behind this behavior is still obscure. Within this context we unexpectedly noticed, predominantly in p53 mutant human cancers, that a subset of highly atypical cancerous cells expressing strongly p21WAF1/Cip1 demonstrated also signs of proliferation. This finding suggests either tolerance to high p21WAF1/Cip1 levels or that p21WAF1/Cip1 per se guided a selective process that led to more aggressive off-springs. To address the latter scenario we employed p21WAF1/Cip1-inducible p53-null cellular models and monitored them over a prolonged time period, using high-throughput screening means. After an initial phase characterized by stalled growth, mainly due to senescence, a subpopulation of p21WAF1/Cip1 cells emerged, demonstrating increased genomic instability, aggressiveness and chemo-resistance. At the mechanistic level unremitted p21WAF1/Cip1 production “saturates” the CRL4CDT2 and SCFSkp2 ubiquitin ligase complexes reducing the turn-over of the replication licensing machinery. Deregulation of replication licensing triggered replication stress fuelling genomic instability. Conceptually, the above notion should be considered when anti-tumor strategies are designed, since p21WAF1/Cip1 responds also to p53-independent signals, including various chemotherapeutic compounds.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.5
作者：
Barlow JH;Faryabi RB;Callén E;Wong N;Malhowski A;Chen HT;Gutierrez-Cruz G;Sun HW;McKinnon P;Wright G;Casellas R;Robbiani DF;Staudt L;Fernandez-Capetillo O;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16.8
作者：
Hanada, Katsuhiro;Budzowska, Magda;Kanaar, Roland
通讯作者：
Kanaar, Roland
影响因子：
12.4
作者：
Evangelou, K.;Bartkova, J.;Gorgoulis, V. G.
通讯作者：
Gorgoulis, V. G.