HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dan, H. C. Articles by Baldwin, A. S. Search for Related Content PubMed PubMed Citation Articles by Dan, H. C. Articles by Baldwin, A. S.

Differential Involvement of IB Kinases and β in Cytokine- and Insulin-Induced Mammalian Target of Rapamycin Activation Determined by Akt¹

Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors such as insulin, cytokines such as TNF, and Akt-dependent signaling associated with oncoprotein expression. mTOR is negatively controlled by the tuberous sclerosis complex 1/2 (TSC1/2), and activation of Akt induces phosphorylation of TSC2, which blocks the repressive TSC1/2 activity. Previously, we showed that activation of mTOR in PTEN-deficient cancer cells involves IB kinase (IKK) , a catalytic subunit of the IKK complex that controls NF-B activation. Recently, a distinct IKK subunit, IKKβ, was shown to phosphorylate TSC1 to promote mTOR activation in an Akt-independent manner in certain cells stimulated with TNF and in some cancer cells. In this study, we have explored the involvement of both IKK and IKKβ in insulin- and TNF-induced mTOR activation. Insulin activation of mTOR requires Akt in a manner that involves IKK, preferentially to IKKβ, and TSC2 phosphorylation. TNF, in most cells examined, activates Akt to use IKK to control mTOR activation. In MCF7 cells, TNF does not activate Akt and requires IKKβ to activate mTOR. The results show that Akt-dependent signaling, induced by cytokines or insulin, alters the IKK subunit-dependent control of mTOR.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (AI35098 and CA75080). A postdoctoral fellowship to H.C.D. from the Department of Defense is acknowledged. Additional support was provided the Samuel Waxman Cancer Research Foundation.

² Address correspondence and reprint requests to Dr. Albert S. Baldwin, Lineberger Comprehensive Cancer Center, Campus Box No. 7295, University of North Carolina, Chapel Hill, NC 27599. E-mail address: abaldwin{at}med.unc.edu

³ Abbreviations used in this paper: mTOR, mammalian target of rapamycin; IKK, IB kinase; TSC, tuberous sclerosis complex; siRNA, short interfering RNA; IKK DKO, IKK double knockout; MEF, mouse embryonic fibroblasts.

This article has been cited by other articles:

				J. Tsai, R. Zhang, W. Qiu, Q. Su, M. Naples, and K. Adeli Inflammatory NF-{kappa}B activation promotes hepatic apolipoprotein B100 secretion: evidence for a link between hepatic inflammation and lipoprotein production Am J Physiol Gastrointest Liver Physiol, June 1, 2009; 296(6): G1287 - G1298. [Abstract] [Full Text] [PDF]

				W. Hu, F. Li, S. Mahavadi, and K. S. Murthy Upregulation of RGS4 expression by IL-1{beta} in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3{beta} pathway Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1310 - C1320. [Abstract] [Full Text] [PDF]

				S. Park, D. Zhao, K. J. Hatanpaa, B. E. Mickey, D. Saha, D. A. Boothman, M. D. Story, E. T. Wong, S. Burma, M.-M. Georgescu, et al. RIP1 Activates PI3K-Akt via a Dual Mechanism Involving NF-{kappa}B-Mediated Inhibition of the mTOR-S6K-IRS1 Negative Feedback Loop and Down-regulation of PTEN Cancer Res., May 15, 2009; 69(10): 4107 - 4111. [Abstract] [Full Text] [PDF]

				M. Minhajuddin, K. M. Bijli, F. Fazal, A. Sassano, K. I. Nakayama, N. Hay, L. C. Platanias, and A. Rahman Protein Kinase C-{delta} and Phosphatidylinositol 3-Kinase/Akt Activate Mammalian Target of Rapamycin to Modulate NF-{kappa}B Activation and Intercellular Adhesion Molecule-1 (ICAM-1) Expression in Endothelial Cells J. Biol. Chem., February 13, 2009; 284(7): 4052 - 4061. [Abstract] [Full Text] [PDF]