| Autor: |
Galanos, P. Vougas, K. Walter, D. Polyzos, A. Maya-Mendoza, A. Haagensen, E.J. Kokkalis, A. Roumelioti, F.-M. Gagos, S. Tzetis, M. Canovas, B. Igea, A. Ahuja, A.K. Zellweger, R. Havaki, S. Kanavakis, E. Kletsas, D. Roninson, I.B. Garbis, S.D. Lopes, M. Nebreda, A. Thanos, D. Blow, J.J. Townsend, P. SØrensen, C.S. Bartek, J. Gorgoulis, V.G. |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Popis: |
The cyclin-dependent kinase inhibitor p21 WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery - an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs. © 2016 Macmillan Publishers Limited. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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