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

Mol Cell. 2005 Apr 1;18(1):71-82. doi: 10.1016/j.molcel.2005.03.006.

Abstract

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.

MeSH terms

  • Apoptosis
  • Base Sequence
  • Cell Division
  • Cell Line, Tumor
  • Cyclin D1 / genetics
  • DNA Primers
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / metabolism
  • Gene Expression Regulation*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • I-kappa B Kinase
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Estrogen / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection

Substances

  • DNA Primers
  • Estrogen Receptor alpha
  • Receptors, Estrogen
  • Cyclin D1
  • Estradiol
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human