Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2
- Brendan D. Manning1,5,
- M. Nicole Logsdon1,
- Alex I. Lipovsky1,
- Derek Abbott2,3,
- David J. Kwiatkowski4, and
- Lewis C. Cantley2
- 1Department of Genetics and Complex Diseases, Harvard School of Public Health; 2Department of Systems Biology, Harvard Medical School; Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center; 3Department of Pathology, 4Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Abstract
The PTEN and TSC2 tumor suppressors inhibit mammalian target of rapamycin (mTOR) signaling and are defective in distinct hamartoma syndromes. Using mouse genetics, we find that Pten and Tsc2 act synergistically to suppress the severity of a subset of tumors specific to loss of each of these genes. Interestingly, we find that the slow-growing tumors specific to Tsc2+/- mice exhibit defects in signaling downstream of Akt. However, Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity. This study demonstrates that attenuation of the PI3K-Akt pathway in tumors lacking TSC2 contributes to their benign nature.
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Footnotes
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Supplemental material is available at http://www.genesdev.org.
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Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1314605.
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↵5 Corresponding author. E-MAIL bmanning{at}hsph.harvard.edu; FAX (617) 432-5236.
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- Accepted June 7, 2005.
- Received March 11, 2005.
- Cold Spring Harbor Laboratory Press
