Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.