PROGRESSIVE ELEVATION OF AP-1 ACTIVITY DURING PRENEOPLASTIC-TO-NEOPLASTIC PROGRESSION AS MODELED IN MOUSE JB6 CELL VARIANTS

The JB6 mouse epidermal cell system has been used extensively as an in vitro model for the study of tumor promotion and progression. The pre sent study was directed to assessing the role of basal AP-1 activity i n JB6 variants which represent preneoplastic to neoplastic progression and to addressing whether AP-1 activity is required for maintenance o f the tumor phenotype. Constitutively higher AP-1 activity was found i n tumorigenic JB6 RT101 cells than in later or earlier preneoplastic P + or P- cells. Levels of c-jun mRNA and protein correlated with progre ssion stage. Enhancement of AP-1 activity by TPA increased the formati on of anchorage independent colonies by tumorigenic RT101 cells. Inhib ition of AP-1 activity by retinoic acid or fluocinolone acetonide inhi bited expression of tumor phenotype as measured by AI growth. These da ta together with our previous results suggest that in the JB6 model (i ) basal levels of Jun and AP-1 appear to be important for preneoplasti c-to-neoplastic progression; (ii) induced AP-1 appears to be required for further progression by tumor cells; (iii) constitutively elevated AP-I activity may be important for the expression of transformed pheno type; (iv) inhibition of AP-1 activity by RA or FA is not a general su ppression of transcription but is gene-specific; and (v) even though b oth inhibition of AP-1 activity and activation of RARE-dependent or GR E-dependent gene transcription correlate with inhibition of AI growth in RT101 cells by RA or FA, transactivation of RARE or GRE might bette r correlate with the inhibition of AI growth than the inhibition of AP -1 activity in RT101 cells.