Up-regulation of a mutant form of p53 by doxorubicin in human squamous carcinoma cells.
Human squamous carcinoma A431 cells express a high level of epidermal growth factor (EGF) receptor. The cells carry only a mutated form of the p53 gene, the G-->A mutation at codon 273 which results in an arginine to histidine substitution (mp53). The temporal changes of EGF receptor, c-Raf-1, mp53, and cell cycle distribution in A431 cells after 1-h exposure to doxorubicin (DOX) are examined. EGF receptor in A431 cells is inactivated at 5 min; subsequently, the receptor level increases and reaches its maximum 4-8 h after DOX treatment. Dephosphorylation of c-Raf-1 is detected at 30 min and the decay of the protein is demonstrated at 8 h in cells after exposure to DOX. The level of mp53 in A431 cells remains unchanged for 8 h after DOX treatment but increases by about 20-fold at 24 h. There is no significant change in cell cycle distribution in A431 cells for up to 8 h after DOX exposure, whereas cells are accumulated in S and G2-M phases by 24 h. It is postulated that DOX inactivates EGF signal transduction and induces mp53. The increase in mp53 is coincident with DOX-induced G2-M block in cells.
Kwok
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Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115.
Mok
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Menton-Brennan
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D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002453:Cell Cycle; D004317:Doxorubicin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf