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.
Dan
Han C
HC
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Cooper
Matthew J
MJ
Cogswell
Patricia C
PC
Duncan
Joseph A
JA
Ting
Jenny P-Y
JP
Baldwin
Albert S
AS
D048868:Adaptor Proteins, Signal Transducing; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D011506:Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D020123:Sirolimus