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

Gan, B. Y., Lim, C., Chu, G., Hua, S. J., Ding, Z. H., Collins, M., Hu, J. A., Jiang, S., Fletcher-Sananikone, E., Zhuang, L., Chang, M., Zheng, H. W., Wang, Y. A., Kwiatkowski, D. J., Kaelin, W. G., Signoretti, S., DePinho, R. A. (November 2010) FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis. Cancer Cell, 18 (5). pp. 472-484. ISSN 1535-6108

URL: http://www.ncbi.nlm.nih.gov/pubmed/21075312
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 Fox Os; 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-SR alpha and mir-145, establishing a FoxO-Mxi1-SR alpha/mir-145 axis as a major progression block in renal tumor development.

Item Type: Paper
Uncontrolled Keywords: MTOR SIGNALING PATHWAY CLEAR-CELL CARCINOMA C-MYC TRANSCRIPTIONAL REPRESSION HISTONE DEACETYLASE TUMOR SUPPRESSION GENE-EXPRESSION HUMAN CANCERS N-COR METABOLISM Oncology Cell Biology
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: November 2010
Date Deposited: 22 Aug 2014 19:05
Last Modified: 22 Aug 2014 19:05
PMCID: PMC3023886
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30702

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