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FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis
- Publication Year :
- 2010
-
Abstract
- SummarymTORC1 is a validated therapeutic target for renal cell carcinoma (RCC). Here, analysis of Tsc1-deficient (mTORC1 hyperactivation) mice uncovered a FoxO-dependent negative feedback circuit constraining mTORC1-mediated renal tumorigenesis. We document robust FoxO activation in Tsc1-deficient benign polycystic kidneys and FoxO extinction on progression to murine renal tumors; murine renal tumor progression on genetic deletion of both Tsc1 and FoxOs; and downregulated FoxO expression in most human renal clear cell and papillary carcinomas, yet continued expression in less aggressive RCCs and benign renal tumor subtypes. Mechanistically, integrated analyses revealed that FoxO-mediated block operates via suppression of Myc through upregulation of the Myc antagonists, Mxi1-SRα and mir-145, establishing a FoxO-Mxi1-SRα/mir-145 axis as a major progression block in renal tumor development.
- Subjects :
- Transcriptional Activation
Cancer Research
Apoptosis
mTORC1
Biology
Mechanistic Target of Rapamycin Complex 1
medicine.disease_cause
urologic and male genital diseases
Article
Tuberous Sclerosis Complex 1 Protein
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Renal cell carcinoma
microRNA
medicine
Basic Helix-Loop-Helix Transcription Factors
Tumor Cells, Cultured
Animals
Humans
Carcinoma, Renal Cell
030304 developmental biology
0303 health sciences
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins
fungi
Cancer
Proteins
Forkhead Transcription Factors
Cell Biology
medicine.disease
Kidney Neoplasms
Gene Expression Regulation, Neoplastic
MicroRNAs
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Multiprotein Complexes
embryonic structures
Cancer research
TSC1
biological phenomena, cell phenomena, and immunity
Carcinogenesis
Clear cell
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....510607a67172bee09bc54470323d0e84