Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA322499 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:P53 independent P21 expression deregulates replication licensing , leading to genomic instability
2016-05-17 | PXD004140 | Pride
Project description:Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability
| PRJNA322497 | ENA
Project description:Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability II
| PRJNA322498 | ENA
Project description: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, through a so-far obscure mechanism, p21 could also be oncogenic. 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 chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal 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.
2016-05-24 | GSE81753 | GEO
Project description: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, through a so-far obscure mechanism, p21 could also be oncogenic. 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 chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal 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.
2016-05-24 | GSE81752 | GEO
Project description: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
2016-05-15 | E-GEOD-62166 | biostudies-arrayexpress
Project description: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 “saturates” 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.
2016-05-15 | GSE62166 | GEO
Project description:The maintenance of genome stability relies on the coordinated control of origin activation and replication fork progression. How the interplay between these processes impacts human genetic disease and cancer remains incompletely characterized. Here we initially show that mouse cells lacking Pole4 and featuring Pole instability exhibit impaired genome-wide activation of DNA replication origins, in a origin location-independent manner. Lack of POLE4 leads to proteasome-dependent Pole degradation prior to CMG (CDC45/MCM2-7/GINS) helicase formation and origin activation. Strikingly, Trp53 ablation in primary Pole4 knock-out cells increased Pole levels and origin activation and reduced DNA damage levels in a transcription-dependent manner. Transcriptome analysis of primary Trp53 knock out cells revealed that the TRP53-CDKN1A/P21 axis maintains appropriate levels of replication initiation factors and CDK activity during unchallenged S-phase. Loss of this control mechanism deregulates origin activation, perturbs genome-wide replication fork progression and induces fork stalling and DNA damage. Thus, while our data support an impaired origin activation model for genetic diseases affecting CMG formation, we propose that loss of the TRP53-CDKN1A/P21 tumour suppressor axis induces inappropriate origin activation and deregulates genome wide fork progression. This phenomenon has broad implications for genetic instability and therapeutic targeting in cancer.
2022-05-16 | GSE200331 | GEO
Project description:Long non-coding RNA ESRG was first identified in our previous study, but its physiological function, regulatory and action mechanisms in human pluripotent stem cells (hPSCs) remain largely unexplored. Here, we found that ESRG is specifically and highly expressed in hPSCs, and its transcription is directly regulated by OCT4, suggesting that ESRG may be an integral component of the core regulatory circuit regulating the pluripotent state of hPSCs. Knockdown of ESRG induces hPSC differentiation, cell cycle arrest, and apoptosis. Mechanistically, ESRG binds to minichromosome maintenance protein 2 (MCM2), a replication-licensing factor, to sustain its steady-state level and nuclear translocation, safeguarding error-free DNA replication. Further study showed that inhibition of the interaction bewteen ESRG and MCM2 results in DNA damage and activation of p53 signaling pathway, ultimately deregulates deregulates pluripotency and self-renewal of hPSCs. In sum, our observations suggest that ESRG, as a novel target of OCT4, plays an essential role in maintaining the pluripotency and self-renewal of hPSCs in collaboration with MCM2 to suppress p53 signaling. These findings provide critical insights into the mechanisms underlying the maintenance of self-renewal and pluripotency in hPSCs.
2023-03-02 | GSE190957 | GEO