Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK

  1. Han C. Dan1,
  2. Matthew J. Cooper1,2,
  3. Patricia C. Cogswell1,
  4. Joseph A. Duncan1,
  5. Jenny P.-Y. Ting1, and
  6. Albert S. Baldwin1,2,3,4
  1. 1 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
  2. 2 Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
  3. 3 Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA

Abstract

While NF-κB 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-κB 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-κB 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.

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