Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/105630
Title: Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
Author: Galanos, Panagiotis
Vougas, Konstantinos
Walter, David
Polyzos, Alexander
Maya-Mendoza, Apolinar
Haagensen, Emma J.
Kokkalis, Antonis
Roumelioti, Fani-Marlen
Gagos, Sarantis
Tzetis, Maria
Canovas, Begoña
Igea, Ana
Ahuja, Akshay K.
Zellweger, Ralph
Havaki, Sofia
Kanavakis, Emanuel
Kletsas, Dimitris
Roninson, Igor B.
Garbis, Spiros D.
Lopes, Massimo
Nebreda, Àngel R.
Thanos, Dimitris
Blow, J. Julian
Townsend, Paul
Sørensen, Claus Storgaard
Bartek, Jiri
Gorgoulis, Vassilis G.
Keywords: Càncer
Expressió gènica
Cancer
Issue Date: 20-Jun-2016
Publisher: Macmillan
Abstract: The cyclin-dependent kinase inhibitor p21WAF1/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.
Note: Versió postprint del document publicat a: http://dx.doi.org/10.1038/ncb3378
It is part of: Nature Cell Biology, 2016, num. 18, p. 777–789
Related resource: http://dx.doi.org/10.1038/ncb3378
URI: http://hdl.handle.net/2445/105630
Appears in Collections:Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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