Absence of p53-mediated G1 arrest with induction of MDM2 in sterigmatocystin-treated cells.
P53 plays a critical role in G1 checkpoint after DNA damage. MDM2 gene is a p53 target gene and its protein forms a feedback loop with p53 and inhibits p53-mediated G1 arrest. Sterigmatocystin (ST) is a mycotoxin and carcinogen. In this study we show that exposure of cells to ST for 12 or 24 h resulted in failure of G1 arrest at both time points. Accordingly, p53 protein was not increased and p21WAF1 expression was inhibited at 12 h, and both proteins were weakly induced at 24 h after treatment with ST. Meanwhile, MDM2 protein was induced in a p53-dependent fashion by ST at both 12 and 24 h. The induction of MDM2 was coincident with the cellular responses of p53 and p21WAF1, and might contribute to the failure of G1 arrest in ST-treated cells. In addition, ST-treated cells exhibited G2M arrest, regardless of p53 status. Our results indicate that the carcinogenic effects of ST seem to be mediated by failure of p53-mediated G1 checkpoint.
Xie
T X
TX
Department of Public Health and Hygiene, Oita Medical University, Hasama, Oita 879-5593, Japan.
Misumi
J
J
Aoki
K
K
Zhao
W Y
WY
Liu
S Y
SY
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013241:Sterigmatocystin / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D013241:Sterigmatocystin; D004247:DNA; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2