Synergistic activation of the serotonin-1A receptor by nuclear factor-kappa B and estrogen.
Estrogen exerts profound effects on mood and mental state. The ability of estrogen to modulate serotonergic function raises the possibility that it may play a role in the mechanism associated with depression and its treatment. A cellular mechanism for estrogen to influence mood might be through the regulation of genes involved at various levels of the serotonin system. Here we report that estrogen can up-regulate the expression of the serotonin-1A receptor via a new mechanism involving synergistic activation by nuclear factor-kappa B (NF-kappa B) with estrogen receptor alpha. Interestingly, we observed that only estrogen receptor-alpha, and not -beta, was able to mediate this effect of estrogens. The partial antiestrogen, 4-hydroxytamoxifen, had the same effect as estrogen. In addition, mutation analysis showed that both the transactivation function of p65 and activation function 1 of estrogen receptor-alpha were essential for this synergistic regulation. Therefore, we propose that NF-kappa B complexes cooperate with estrogen receptor-alpha to recruit cofactors into the complex and thereby synergistically activate the serotonin-1A receptor promoter through nonclassical estrogen response elements by a mechanism that does not involve direct receptor binding to DNA.
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands.
S
S
Wissink
B
B
van der Burg
B S
BS
Katzenellenbogen
P T
PT
van der Saag
D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D016328:NF-kappa B; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C051781:ICI 164384