Estrogen receptors (ER alpha and ER beta) mediate opposite functions on cancer growth induced by 17 beta-estradiol (E2). E2 binding to ER alpha induces a cancer promoting response, whereas E2 binding to ERP exerts a protective action against cancer growth. Moreover, E2 can diversely modulate the ER alpha and ERP levels intensifying or decreasing their actions in target tissues. Only molecular mechanisms at the root of E2 ability to down-regulate the ERa levels are known. Here, we report the first molecular mechanism underlying E2-induced ER beta up-regulation in DLD-1 colon cancer cells. E2 induces a short term (2 and 4 h after stimulation) translation of ER beta mRNA followed by a late (24 h after stimulation) enhanced transcription. Both processes required the E2-induced persistent and palmitoyl ation -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. (C) 2007 Elsevier Inc. All rights reserved.