Several signaling molecules have been identified which act as inhibitors of epithelial cell growth. The mechanisms for this negative growth regulation are still poorly understood. In the case of TGF-beta, inhibition of keratinocyte cell growth can be totally prevented by transformation with an intact early region 1a (E1a) oncogene. We show here that E1a-transformed keratinocytes become also partially resistant to growth inhibition by elevated 3',5'-cyclic adenosine monophosphate (cAMP) levels, as induced by treatment with forskolin, dibutyryl-cAMP, 8Br-cAMP, or 8Cl-cAMP. Resistance to cAMP is due to interference of E1a with signaling pathways downstream of protein kinase A (PKA) activation, as intracellular cAMP levels and PKA activity were found to be similar in control and E1a-transformed cells. Induction of c-fos expression by 8Br-cAMP occurs at the same time in both cell lines. Interestingly however, this effect is maintained longer in the case of E1a-transformed cells compared to the control. A truncated E1a mutant which is still able to bind to the p105-Rb gene product, p107, and p60/cyclin A, induces cAMP resistance at levels which are only slightly lower than those induced by an intact E1a oncogene. In contrast, an E1a mutant which binds only to a p300 cellular protein and induces a substantial level of TGF-beta resistance fails to induce cAMP resistance. Thus, E1a transformation counteracts the growth-inhibitory effects of cAMP as well as TGF-beta, but to a different degree and through an only partially overlapping mechanism.