EARLY ULTRAVIOLET B-INDUCED G1 ARREST AND SUPPRESSION OF THE MALIGNANT PHENOTYPE BY WILD-TYPE P53 IN HUMAN SQUAMOUS-CELL CARCINOMA-CELLS

Wild-type p53 (wt-p53) negatively controls cell cycle progression afte r cellular stress mediating either a temporary growth arrest or apopto sis, depending on the cell type and nature of the cellular stress. The aberrant proliferation which is characteristic of tumor cells may be suppressed by exogenous wt-p53 and appears to depend strongly on the l evel of reexpression. We performed retroviral-mediated gene transfer o f wt-p53 into a human squamous cell carcinoma cell line from the head and neck region (A253 cell line) lacking endogenous p53. This allowed us to study the effect of wt-p53 on the malignant phenotype and on the response to the DNA damaging agent ultraviolet B (UVB). Restoration o f wt-p53 in malignant keratinocytes suppressed tumorigenicity in nude mice although p53-reconstituted cells eventually formed small tumors w ith long latency. Cells derived from these tumors showed reduced expre ssion of wt-p53. Exogenous wt-p53 increased baseline mRNA expression o f the small proline rich proteins 1 and 2, consistent with a prodiffer entiating effect. After exposure to a biological WE dose, only p53-pos itive A253 cells underwent an early and transient G1 arrest. Both p53- positive and -negative A253 cells displayed a late G2 delay/arrest. We conclude that reexpression of wt-p53 in squamous cell carcinoma A253 cells decreases their malignant phenotype and reestablishes a G1 check point after UVB. (C) 1997 Academic Press.