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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Gene Expression Regulation, HeLa Cells, Humans, I-kappa B Kinase, Male, NF-kappa B, Prostatic Neoplasms, Protein Kinases, Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Tumor Cells, Cultured
Genes Dev.
Date: Jun. 01, 2008
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