Formation of an IKKα-dependent transcription complex is required for estrogen receptor-mediated gene activation

The IKB kinases IKK alpha and IKK beta regulate distinct cytoplasmic and nuclear events that are critical for cytokine-mediated activation of the NF-B-K pathway. Because the IKKs have previously been demonstrated to associate with the nuclear hormone receptor coactivator AIB1/SRC-3, the question of whether either IKK alpha or IKK beta may be involved in increasing the expression of hormone-responsive genes was addressed. We demonstrated that IKKa, in conjunction with ER alpha. 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 IKK alpha, ER alpha and AIB1/SRC-3 to estrogen-responsive promoters and increased IKK alpha phosphorylation of ERet, AlB1/ SRC-3, and histone H3. These results suggest that IKK alpha plays a major role in regulating the biological effects of estrogen via its promoter association and modification of components of the transcription complex.