Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor alpha.
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.
Gallo
Dominique
D
Laboratoire J.-C. Heuson de Cancérologie Mammaire, Université Libre de Bruxelles, Institut Jules Bordet, 1 rue Héger-Bordet, B-1000 Brussels, Belgium.
Jacquemotte
Françoise
F
Cleeren
Anny
A
Laïos
Ioanna
I
Hadiy
Samira
S
Rowlands
Martin G
MG
Caille
Olivier
O
Nonclercq
Denis
D
Laurent
Guy
G
Jacquot
Yves
Y
Leclercq
Guy
G
D000595:Amino Acid Sequence; D001665:Binding Sites; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000819:agonists*; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion; D014158:Transcription, Genetic
D002147:Calmodulin; D047628:Estrogen Receptor alpha; D010455:Peptides