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The University of Southampton
Institute for Life Sciences

'The Dark Side of p21', in Nature Cell Biology

Published: 28 June 2016
The dark side of p21

Congratulations to Dr Spiros D Garbis, Associate Professor and Head of the Proteomics Unit for Cancer Sciences, Centre for Proteomics Research and Institute for Life Sciences member, on the publication of his group's five-year research project in Nature Cell Biology: UK Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.

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.

Dr Spiros Garbis
Dr Spiros Garbis, Cancer Sciences, IfLS Member
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