Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor alpha
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Calmodulin (CaM) contributes to estrogen receptor alpha (ER)-mediated transcription. In order to study the underlying mechanisms, we synthesized a peptide including the CaM binding site: ERalpha17p (P(295)-T(311)). This peptide inhibited ER-CaM association, unlike two analogs in which two amino acids required for CaM binding were substituted. Exposure of MCF-7 cells to ERalpha17p down regulated ER, stimulated ER-dependent transcription and enhanced the proliferation of ER-positive breast cancer cell lines. Interestingly, ERalpha17p analogs unable to bind to CaM induced similar responses, demonstrating that ERalpha17p-mediated effects are mainly relevant to mechanisms independent of ER-CaM dissociation. The P(295)-T(311) motif is indeed a platform for multiple post-translational modifications not necessarily CaM-dependent. The additional finding that deletion of the P(295)-T(311) sequence in ER produced a constitutive transcriptional activity revealed that this platform motif has autorepressive functions. With regard to cell function, association of CaM to ER would counteract this autorepression, leading thereby to enhanced ER-mediated transactivation.
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Estrogen receptor alpha; calmodulin; peptide; breast cancer
Hit Discovery & Structural Design
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MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2007, 268 (1-2), pp. 37 - 49