Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK

Genes Dev. 2008 Jun 1;22(11):1490-500. doi: 10.1101/gad.1662308.

Abstract

While NF-kappaB is considered to play key roles in the development and progression of many cancers, the mechanisms whereby this transcription factor is activated in cancer are poorly understood. A key oncoprotein in a variety of cancers is the serine-threonine kinase Akt, which can be activated by mutations in PI3K, by loss of expression/activity of PTEN, or through signaling induced by growth factors and their receptors. A key effector of Akt-induced signaling is the regulatory protein mTOR (mammalian target of rapamycin). We show here that mTOR downstream from Akt controls NF-kappaB activity in PTEN-null/inactive prostate cancer cells via interaction with and stimulation of IKK. The mTOR-associated protein Raptor is required for the ability of Akt to induce NF-kappaB activity. Correspondingly, the mTOR inhibitor rapamycin is shown to suppress IKK activity in PTEN-deficient prostate cancer cells through a mechanism that may involve dissociation of Raptor from mTOR. The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • Male
  • NF-kappa B / metabolism*
  • Prostatic Neoplasms
  • Protein Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / physiology*
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • NF-kappa B
  • Proteins
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • Protein Kinases
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • Sirolimus