Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest.
Cell Cycle Checkpoints
/ drug effects
Cell Line
Cyclin-Dependent Kinase 2
/ metabolism
Cyclin-Dependent Kinase Inhibitor p21
/ metabolism
Down-Regulation
/ drug effects
E2F1 Transcription Factor
/ metabolism
E2F4 Transcription Factor
/ metabolism
Environmental Pollutants
/ toxicity
Gene Expression Regulation
/ drug effects
Gene Regulatory Networks
/ drug effects
Humans
Ochratoxins
/ toxicity
Phenotype
CDK2
CDKN1A/p21
WGCNA
cell cycle
human kidney
nephrotoxicity
ochratoxin A
transcriptomics
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
07 01 2020
07 01 2020
Historique:
received:
09
12
2019
revised:
20
12
2019
accepted:
23
12
2019
entrez:
16
1
2020
pubmed:
16
1
2020
medline:
16
1
2021
Statut:
epublish
Résumé
Environmental food contaminants constitute a threat to human health. For instance, the globally spread mycotoxin Ochratoxin A (OTA) contributes to chronic kidney damage by affecting proximal tubule cells via unknown mechanisms. We applied a top-down approach to identify relevant toxicological mechanisms of OTA using RNA-sequencing followed by in-depth bioinformatics analysis and experimental validation. Differential expression analyses revealed that OTA led to the regulation of gene expression in kidney human cell lines, including for genes enriched in cell cycle-related pathways, and OTA-induced gap 1 and 2 (G1 and G2) cell-cycle arrests were observed. Weighted correlation network analysis highlighted cyclin dependent kinase 2 (CDK2) as a putative key regulator of this effect. CDK2 was downregulated by OTA exposure, and its overexpression partially blocked the OTA-induced G1 but not G2 cell-cycle arrest. We, therefore, propose CDK2 as one of the key regulators of the G1 cell-cycle arrest induced by low nanomolar concentrations of OTA.
Identifiants
pubmed: 31936152
pii: cells9010143
doi: 10.3390/cells9010143
pmc: PMC7017252
pii:
doi:
Substances chimiques
CDKN1A protein, human
0
Cyclin-Dependent Kinase Inhibitor p21
0
E2F1 Transcription Factor
0
E2F1 protein, human
0
E2F4 Transcription Factor
0
E2F4 protein, human
0
Environmental Pollutants
0
Ochratoxins
0
ochratoxin A
1779SX6LUY
Cyclin-Dependent Kinase 2
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
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