Protracted p53-independent stimulation of p21WAF1/Cip1 fuels genomic instability by deregulating the replication licensing machinery

ABSTRACT: 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 â??saturatesâ?? 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. We used microarrays to compare the non-induced and â??escapedâ?? Saos2-p21WAF1/Cip1 Tet-ON cells gene expression profile Multiple arrays for non-induced and â??escapedâ?? Saos2-p21WAF1/Cip1 Tet-ON cells

ORGANISM(S): Homo sapiens

SUBMITTER: Alexander Polyzos 

PROVIDER: E-GEOD-62166 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress