Synergistic activation of the serotonin-1A receptor by nuclear factor-kappa B and estrogen

S Wissink, B van der Burg, B S Katzenellenbogen, P T van der Saag

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)543-52
Number of pages10
JournalMolecular endocrinology (Baltimore, Md.)
Issue number4
StatePublished - Apr 2001


  • Animals
  • Cells, Cultured
  • Estradiol/analogs & derivatives
  • Estrogen Antagonists/pharmacology
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens/metabolism
  • Humans
  • NF-kappa B/metabolism
  • Polyunsaturated Alkamides
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Receptors, Estrogen/drug effects
  • Receptors, Serotonin/drug effects
  • Receptors, Serotonin, 5-HT1
  • Tamoxifen/analogs & derivatives
  • Transcriptional Activation


Dive into the research topics of 'Synergistic activation of the serotonin-1A receptor by nuclear factor-kappa B and estrogen'. Together they form a unique fingerprint.

Cite this