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FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 May 21; Vol. 285 (21), pp. 15960-5. Date of Electronic Publication: 2010 Apr 06. - Publication Year :
- 2010
-
Abstract
- Akt signal transduction induces coordinated increases in glycolysis and apoptosis resistance in a broad spectrum of cancers. Downstream of Akt, the FoxO transcription factors regulate apoptosis via Bim, but the contributions of FoxOs in regulating Akt-induced glycolysis are not well described. We find that FoxO3a knockdown is sufficient to induce apoptosis resistance in conjunction with elevated glycolysis. Glycolysis in FoxO3a-deficient cells was associated with increased S6K1 phosphorylation and was sensitive to rapamycin, an inhibitor of the mTORC1 pathway that has been linked to glycolysis regulation. We show that mTORC1-dependent glycolysis is increased in FoxO3a knockdown cells due to decreased expression of the TSC1 tumor suppressor that opposes mTORC1 activation. FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1.
- Subjects :
- Animals
Cell Line
Forkhead Box Protein O3
Forkhead Transcription Factors genetics
Glycolysis drug effects
Humans
Immunosuppressive Agents pharmacology
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes
Phosphorylation drug effects
Phosphorylation physiology
Promoter Regions, Genetic physiology
Proteins
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Ribosomal Protein S6 Kinases genetics
Ribosomal Protein S6 Kinases metabolism
Sirolimus pharmacology
TOR Serine-Threonine Kinases
Transcription Factors antagonists & inhibitors
Transcription Factors genetics
Transcription Factors metabolism
Transcription, Genetic drug effects
Transcriptional Activation drug effects
Tuberous Sclerosis Complex 1 Protein
Tumor Suppressor Proteins genetics
Forkhead Transcription Factors metabolism
Glycolysis physiology
Transcription, Genetic physiology
Transcriptional Activation physiology
Tumor Suppressor Proteins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20371605
- Full Text :
- https://doi.org/10.1074/jbc.M110.121871