| Title | FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Gan B, Lim C, Chu G, Hua S, Ding Z, Collins M, Hu J, Jiang S, Fletcher-Sananikone E, Zhuang L, Chang M, Zheng H, Y Wang A, Kwiatkowski DJ, Kaelin WG, Signoretti S, DePinho RA |
| Journal | Cancer Cell |
| Volume | 18 |
| Issue | 5 |
| Pagination | 472-84 |
| Date Published | 2010 Nov 16 |
| ISSN | 1878-3686 |
| Keywords | Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Forkhead Transcription Factors, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mice, MicroRNAs, Multiprotein Complexes, Proteins, Proto-Oncogene Proteins c-myc, Signal Transduction, TOR Serine-Threonine Kinases, Transcriptional Activation, Tuberous Sclerosis Complex 1 Protein, Tumor Cells, Cultured, Tumor Suppressor Proteins |
| 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. |
| DOI | 10.1016/j.ccr.2010.10.019 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 21075312 |
| Grant List | 1P01CA120964 / CA / NCI NIH HHS / United States P50CA101942-06A1 / CA / NCI NIH HHS / United States R21CA135057 / CA / NCI NIH HHS / United States U01CA141508 / CA / NCI NIH HHS / United States |
Related Faculty:
Hongwu Zheng, Ph.D.