The hormonal response of estrogen receptor beta is decreased by the phosphatidylinositol 3-kinase/Akt pathway via a phosphorylation-dependent release of CREB-binding protein.
The hormonal response of estrogen receptors (ER) alpha and ERbeta is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ERbeta activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ERbeta involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ERbeta response to estrogen. Such reduced activity was associated with an impaired ability of ERbeta to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ERbeta, prevented the release of CBP and rendered ERbeta transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ERbeta activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ERbeta. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ERbeta also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence.
Sanchez
Mélanie
M
Research Center, Sainte-Justine Hospital, and the University of Montreal, Montréal H3T 1C5, Québec, Canada.
Sauvé
Karine
K
Research Center, Sainte-Justine Hospital, and the University of Montreal, Montréal H3T 1C5, Québec, Canada.
Picard
Nathalie
N
Research Center, Sainte-Justine Hospital, and the University of Montreal, Montréal H3T 1C5, Québec, Canada.
Tremblay
André
A
Research Center, Sainte-Justine Hospital, and the University of Montreal, Montréal H3T 1C5, Québec, Canada; Departments of Biochemistry and University of Montreal, Montréal H3T 1C5, Québec, Canada; Obstetrics and Gynecology, University of Montreal, Montréal H3T 1C5, Québec, Canada. Electronic address: andre.tremblay@recherche-ste-justine.qc.ca.
D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
D050882:CREB-Binding Protein; D047629:Estrogen Receptor beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C494363:CREBBP protein, human