Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation.
The IkappaB kinases IKKalpha and IKKbeta regulate distinct cytoplasmic and nuclear events that are critical for cytokine-mediated activation of the NF-kappaB pathway. Because the IKKs have previously been demonstrated to associate with the nuclear hormone receptor coactivator AIB1/SRC-3, the question of whether either IKKalpha or IKKbeta may be involved in increasing the expression of hormone-responsive genes was addressed. We demonstrated that IKKalpha, in conjunction with ERalpha and AIB1/SRC-3, is important in activating the transcription of estrogen-responsive genes, including cyclin D1 and c-myc, to result in the enhanced proliferation of breast cancer cells. Estrogen treatment facilitated the association of IKKalpha, ERalpha, and AIB1/SRC-3 to estrogen-responsive promoters and increased IKKalpha phosphorylation of ERalpha, AIB1/SRC-3, and histone H3. These results suggest that IKKalpha plays a major role in regulating the biological effects of estrogen via its promoter association and modification of components of the transcription complex.
Park
Kyu-Jin
KJ
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Krishnan
Venkatesh
V
O'Malley
Bert W
BW
Yamamoto
Yumi
Y
Gaynor
Richard B
RB
D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D019938:Cyclin D1; D004958:Estradiol; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human