Author/Authors :
Gan، نويسنده , , Boyi and Lim، نويسنده , , Carol and Chu، نويسنده , , Gerald and Hua، نويسنده , , Sujun and Ding، نويسنده , , Zhihu and Collins، نويسنده , , Michael Y. Hu، نويسنده , , Jian and Jiang، نويسنده , , Shan and Fletcher-Sananikone، نويسنده , , Eliot and Zhuang، نويسنده , , Li and Chang، نويسنده , , Michelle J Zheng، نويسنده , , Hongwu and Wang، نويسنده , , Y. Alan and Kwiatkowski، نويسنده , , David J. and Kaelin Jr.، نويسنده , , William G. and Signoretti، نويسنده , , Sabina and DePinho، نويسنده , , Ronald A.، نويسنده ,
Abstract :
Summary
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.
