FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

This study reports the engineering of a highly penetrant model of renal adenoma/carcinoma and identification of a FoxO-Myc network as integral regulators of renal tumorigenesis in mice and humans

Boyi Gan; Carol Lim; Gerald Chu; Sujun Hua; Zhihu Ding; Michael Collins; Jian Hu; Shan Jiang; Eliot Fletcher-Sananikone; Li Zhuang; Michelle Chang; Hongwu Zheng; Y. Alan Wang; David J. Kwiatkowski; William G. Kaelin; Sabina Signoretti; Ronald A. DePinho

2010

Scholarcy highlights

  • The mammalian target of rapamycin complex 1 serves as the key regulator of protein synthesis and cell growth via phosphorylation of a variety of downstream targets, including S6 Kinase and 4E-BP1, and plays a critical role in the regulation of cell growth, angiogenesis, and metabolism in many human cancers, including renal cell carcinoma
  • RCC comprises $3% of all adult malignancies, ranks among the top 10 cancers in the United States, and continues to show modest responses to most conventional cancer treatments. mammalian target of rapamycin complex 1 hyperactivation is observed in the majority of human RCC samples and has emerged as a therapeutic target for RCC after several clinical trials establishing clinical benefit of mTORC1 inhibitors
  • FoxOs Are Activated in Tsc1-Deficient Polycystic Kidneys, but Lost in Tsc1-Deficient Renal Adenomas and Carcinomas To better understand the molecular and biological role of mTORC1 hyperactivation in renal cancer development, we assessed the impact of homozygous deletion of Tsc1 conditional knockout allele using the Rosa26-CreERT2 knock-in deletor allele that enables tamoxifen-inducible Cre-mediated excision of conditional knockout alleles in most tissues, including kidneys
  • All Tsc1 KO mice developed bilateral polycystic kidneys with >10-fold weights relative to littermate controls and significantly dilated renal tubules on histopathological analysis, which is consistent with the documented connection between tuberous sclerosis and polycystic kidney disease
  • Myc expression was downregulated in Tsc1 KO polycystic kidneys compared with Tsc1 WT kidneys, there was no obvious difference in Myc protein levels and in expression levels of Myc targets between Tsc1 KO polycystic kidneys and Tsc1 WT kidneys
  • Because mTORC1 hyperactivation is known to promote Myc translation, our data together suggest that, in Tsc1 KO polycystic kidneys with mTORC1 hyperactivation and FoxO activation, Myc protein level is balanced by both increased protein synthesis afforded by mTORC1 hyperactivation and decreased mRNA levels via FoxO activation
  • Integrated analyses revealed that FoxO-mediated block operates via suppression of Myc through upregulation of the Myc antagonists, Mxi1-SRa and mir-145, establishing a FoxO-Mxi1-SRa/mir-145 axis as a major progression block in renal tumor development

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