Cancer Cell 2010,
Gan, Boyi; Lim, Carol; Chu, Gerald; Hua, Sujun; Ding, Zhihu; Collins, Michael; Hu, Jian; Jiang, Shan; Fletcher-Sananikone, Eliot; Zhuang, Li; Chang, Michelle; Zheng, Hongwu; Wang, Y Alan; Kwiatkowski, David J; Kaelin, William G; Signoretti, Sabina; DePinho, Ronald A
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.
Diseases/Pathways annotated by Medline MESH:
Carcinoma, Renal Cell, Kidney Neoplasms
Document information provided by NCBI PubMed
Text Mining Data
renal cell carcinoma (RCC) → mTORC1: " mTORC1
is a validated therapeutic target
for renal cell carcinoma (RCC)
Manually curated Databases
No curated data.