Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2.

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.

• Authors: Brendan D Manning, M Nicole Logsdon, Alex I Lipovsky, Derek Abbott, David J Kwiatkowski, Lewis C Cantley
• Journal: Genes & development (Genes Dev) Vol. 19 Issue 15 Pg. 1773-8 (Aug 01 2005) ISSN: 0890-9369 [Print] United States
• PMID: 16027169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Proto-Oncogene Proteins
• Repressor Proteins
• TSC2 protein, human
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Phosphoric Monoester Hydrolases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Division
• Cell Line, Tumor
• Feedback
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PTEN Phosphohydrolase
• Phosphoric Monoester Hydrolases (genetics, physiology)
• Polymerase Chain Reaction
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Repressor Proteins (genetics, physiology)
• Signal Transduction
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (genetics, physiology)