The discovery of ERp (1), made possible to show that ERa and P mediate different biological actions. appears to be the quantitatively dominant over in bone, cardiovascular system, urogenital tract, kidney, central nervous system, immune system and lung, whereas has a significant role in the reproductive system, both in males and females (2, 3). ERa is over-expressed in more than 60% of BCs. Activation of both receptors by induces and mediated transcription of genes regulated by E-responsive elements (ERE) (1). However, only ERa mediates E2-dependent transcription of genes regulated by API (4) and Sp1 (5). In contrast, ERP specifically mediates JNK inhibition (6).
For all the reasons exposed above, the finding of selective inhibitors of ERa and (5 is of paramount importance, both to identify the roles of each receptor and to eliminate the deleterious effects ofE therapy. Novel ligands that function as selective E or anti-estrogens for ERa or p have been reported (7, 8), and studies providing basis for some differential transcription activities between both receptors have also been published (9).
The interaction of CaM with ER has been demonstrated, and a CaM binding domain has been postulated (10). Since then, several reports have indicated that CaM was essential for the interaction of ERa with DNA, and for activation of responsive promoters (11). We have demonstrated that ERa is tightly bound to CaM. Its transactivation capacity is dependent on CaM, and therefore able to be inhibited by the CaM antagonist W7. In contrast, ERp does not interact with CaM, and its transactivation capacity is not altered by W7. Furthermore, we converted the W7-sensitive into a W7-insensitive by mutating aminoacids located at the putative CaM binding site (12). Remarkably, these lysines are targets for acetylation by p300 (13) and, K303 is mutated to arginine in 34% ofpre-malignant breast lesions (14). ERa (K303R) mutant homodimers, and interestingly, also K30R/wt and K303 A/wt heterodimers show increased sensitivity to E. Moreover, contrary to the wt ERa, API transcriptional activity mediated by both K303R and K303A mutants is inhibited by E2 and OHTAM.
In summary, all these results strongly suggest that these residues (K302, K303) located in the hinge region might play a crucial role in the ERa regulation in vivo and open new ways of searching for ERa inhibitors which do not interfere ERp-mediated functions.
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