WILD-TYPE P53 TUMOR-SUPPRESSOR GENE RESTORES DIFFERENTIATION OF HUMANSQUAMOUS CARCINOMA-CELLS BUT NOT THE RESPONSE TO TRANSFORMING GROWTH-FACTOR-BETA

In order to clarify the role of the p53 tumor suppressor gene in contr olling growth and differentiation of human epithelial cells, we transf ected a wild-type p53 complementary DNA, driven by a dexamethasone-ind ucible mouse mammary tumor virus promoter, into SqCC/Y1 human head-and -neck squamous carcinoma cells. When treated with dexamethasone, 2 of 8 independent clones that contained integrated vector sequences expres sed wild-type p53-specific mRNA as well as nuclear p53 protein. The hi ghest p53 expressor (SqCC/Y1.53.5) was as resistant to inhibition of c ell growth by transforming growth factor beta as control transfectants . Furthermore, these cells continued to proliferate in medium containi ng the combination of 2 mM Ca2+ and 10% (v/v) fetal bovine serum, whic h normally induces terminal differentiation in primary keratinocytes. However, under these same conditions, two of the essential proteins re quired for the formation of the cornified cell envelope were induced. First, in SqCC/Y1.53.1 and -.5 cells, the activity of membrane-associa ted keratinocyte-specific transglutaminase I increased to 3- to 5-fold higher levels than in control transfectants. Second, in SqCC/Y1.53.1 and -.5 cells, the envelope precursor, involucrin, increased to 5 to 8 times the levels attained in control transfectants. Thus, reexpressio n of wild-type p53 does not restore responsiveness of SqCC/Y1 carcinom a cells to growth inhibition but allows cells to reexpress the protein s required for the assembly of the cornified cell envelope.