THE E1A ONCOGENE INDUCES RESISTANCE TO THE EFFECTS OF 1,25-DIHYDROXYVITAMIN D-3 ON INHIBITION OF GROWTH OF MOUSE KERATINOCYTES

1,25-Dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] inhibited DNA synthesis in transformed mouse keratinocytes (Pam212) in a time- and dose-dependen t manner as measured by [H-3]thymidine incorporation. To investigate t he mechanism through which 1,25-(OH)(2)D-3 acts, we examined its effec ts on Pam212 cells further transformed with the E1A oncogene. Here, we show that transformation of the cells with the E1A oncogene induced r esistance to the effects of 1,25-(OH)(2)D-3 on inhibition of growth of Pam212 cells. While 1,25-(OH)2(D3) treatment increased the level of e xpression of vitamin D receptor mRNA 20-fold in parental cells, the E1 A-transformed cells failed to express vitamin D receptor mRNA even aft er treatment with 1,25-(OH)(2)D-3. Transfection of the E1A-transformed cell line with an expression construct encoding the vitamin D recepto r restored receptor expression as well as the inhibition of growth by 1,25-(OH)(2)D-3 These results suggest that one of the mechanisms for a cquisition of 1,25-(OH)(2)D-3 resistance induced by E1A may involve lo ss of vitamin D receptor inducibility by 1,25-(OH)(2)D-3.