Estrogen receptors (ERalpha and ERbeta) mediate opposite functions on cancer growth induced by 17beta-estradiol (E2). E2 binding to ERalpha induces a cancer promoting response, whereas E2 binding to ERbeta exerts a protective action against cancer growth. Moreover, E2 can diversely modulate the ERalpha and ERbeta levels intensifying or decreasing their actions in target tissues. Only molecular mechanisms at the root of E2 ability to down-regulate the ERalpha levels are known. Here, we report the first molecular mechanism underlying E2-induced ERbeta up-regulation in DLD-1 colon cancer cells. E2 induces a short term (2 and 4h after stimulation) translation of ERbeta mRNA followed by a late (24h after stimulation) enhanced transcription. Both processes required the E2-induced persistent and palmitoylation-dependent p38/MAPK activation. Overall, our data suggest a finely tuned control exerted by rapid signals on different cellular molecular events important for the protective effects of E2 against colon cancer growth.