1. Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK.
- Author
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Dan, Han C., Cooper, Matthew J., Cogswell, Patricia C., Duncan, Joseph A., Ting, Jenny P.-Y., and Baldwin, Albert S.
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PROSTATE cancer treatment , *RAPAMYCIN , *CANCER cells , *TRANSCRIPTION factors , *GROWTH factors , *PROTEIN kinases , *GENE expression - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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