Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
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Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. / 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, Angel; Thanos, Dimitris; Blow, J Julian; Townsend, Paul; Sørensen, Claus Storgaard; Bartek, Jiri; Gorgoulis, Vassilis G.
I: Nature Cell Biology, Bind 18, Nr. 7, 07.2016, s. 777-89.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
AU - Galanos, Panagiotis
AU - Vougas, Konstantinos
AU - Walter, David
AU - Polyzos, Alexander
AU - Maya-Mendoza, Apolinar
AU - Haagensen, Emma J
AU - Kokkalis, Antonis
AU - Roumelioti, Fani-Marlen
AU - Gagos, Sarantis
AU - Tzetis, Maria
AU - Canovas, Begoña
AU - Igea, Ana
AU - Ahuja, Akshay K
AU - Zellweger, Ralph
AU - Havaki, Sofia
AU - Kanavakis, Emanuel
AU - Kletsas, Dimitris
AU - Roninson, Igor B
AU - Garbis, Spiros D
AU - Lopes, Massimo
AU - Nebreda, Angel
AU - Thanos, Dimitris
AU - Blow, J Julian
AU - Townsend, Paul
AU - Sørensen, Claus Storgaard
AU - Bartek, Jiri
AU - Gorgoulis, Vassilis G
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/ncb3378
DO - 10.1038/ncb3378
M3 - Journal article
C2 - 27323328
VL - 18
SP - 777
EP - 789
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 7
ER -
ID: 165716928