Summary

In the search for differences between estrogen receptor (ER) a and ERp, we proved that ERa but not ERp directly interacts with calmodulin (CaM) through the hinge region. The transcriptional activity of a mutant unable to interact with CaM becomes insensitive to inhibition by CaM antagonists (W7). These residues are acetylated by p300 and substitution of lysine 302 and 303 with other residues enhance ERa-hormone sensitivity, suggesting that acetylation normally suppresses ligand sensitivity. Also, the somatic mutation K303R has been identified in early pre-malignant breast lesions. ERa K303R normally binds E but shows increased E-induced transcriptional activation and increased proliferation in response to E when transfected into breast cancer cell (BC) lines. Herein, we show that mutations K303R and K303 A, renderan ERa unable to interact with CaM and therefore insensitive to W7. K303 homodimers and K303 mutant/wt heterodimers show increased sensitivity to E. Contrary to the wt ERa, API transcriptional activity is inhibited by estradiol (E2) and OH-Tamoxifen (OH-TAM) in both K303R and K303 A mutants.

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