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 t he p53 gene, the G-->A mutation at codon 273 which results in an argin ine to histidine substitution (mp53). The temporal changes of EGF rece ptor, c-Raf-l, mp53, and cell cycle distribution in A431 cells after 1 -h exposure to doxorubicin (DOX) are examined. EGF receptor in A431 ce lls is inactivated at 5 min; subsequently, the receptor level increase s 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 demo nstrated at 8 h in cells after exposure to DOX. The level of mp53 in A 431 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 G(2)-M phases by 24 h. It is postulated that DOX inactivates EGF signal transduction and induces mp53. The in crease in mp53 is coincident with DOX-induced G(2)-M block in cells.