IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Cell. 2004 Apr 16;117(2):225-37. doi: 10.1016/s0092-8674(04)00302-2.

Abstract

Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IkappaB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKbeta or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKbeta promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Carcinoma / enzymology
  • Carcinoma / genetics
  • Cell Division / genetics
  • Cell Nucleus / metabolism*
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Feedback, Physiological / genetics
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • I-kappa B Kinase
  • Mice
  • Mice, Nude
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Multienzyme Complexes
  • Proto-Oncogene Proteins
  • Transcription Factors
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex