FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis

Cancer Cell. 2010 Nov 16;18(5):472-84. doi: 10.1016/j.ccr.2010.10.019.

Abstract

mTORC1 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Forkhead Transcription Factors / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology
  • Multiprotein Complexes
  • Proteins / metabolism
  • Proteins / physiology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins c-myc / physiology
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcriptional Activation
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • MIRN145a microRNA, mouse
  • MicroRNAs
  • Multiprotein Complexes
  • Mxi1 protein, mouse
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases