CONTRIBUTION OF ENHANCED TRANSCRIPTIONAL ACTIVATION BY ER TO [(12)VAL] K-RAS MEDIATED NIH3T3 CELL-TRANSFORMATION

We investigated the biological significance of estrogen receptors (ER) in NM3T3 cell transformation by the [(12)Val] K-Ras mutant, This muta nt enhanced the steady state level of ER, Cells expressing mutant K-Ra s (K12V cell) were tumorigenic, To determine the role of ER accumulati on in Ras-transformed cells, we developed cells (KwtER cells) that ove rexpressed both wild-type (wt) K-Ras and ER, and found these cells wer e also tumorigenic. E-2 stimulated the transcriptional activity by ER dominantly in K12V cells, However, only partial activation of ER by E- 2 was seen in KwtER cells, In the presence of 10% serum in media, the activation of ER appeared only in transformed KtwER and K12V cells, su ggesting that two independently transmitted signals, the E-2-ER bindin g and the ER-AF1 activation, are necessary for ER activation and that the dominant activation of ER might be involved in Ras-mediated cell t ransformation, Co-expression of progesterone receptor (PR) with mutant K-Ras led to suppression of tumorigenicity and inhibition of the acti vation of ER, The antisense oligomers complementary to the ER suppress ed proliferation and transformed phenotypes of K12V cells, These obser vations support the importance of ER in aas-mediated cell transformati on.