Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK
- Han C. Dan1,
- Matthew J. Cooper1,2,
- Patricia C. Cogswell1,
- Joseph A. Duncan1,
- Jenny P.-Y. Ting1, and
- Albert S. Baldwin1,2,3,4
- 1 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
- 2 Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
- 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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Footnotes
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↵4 Corresponding author.
↵4 E-MAIL abaldwin{at}med.unc.edu; FAX (919) 966-0444.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1662308.
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- Received February 11, 2008.
- Accepted April 4, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press