FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis

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

doi:10.1016/j.ccr.2010.10.019

FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis

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

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

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.

Original language	English (US)
Pages (from-to)	472-484
Number of pages	13
Journal	Cancer cell
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.10.019
State	Published - Nov 16 2010

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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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., Wang, Y. A., Kwiatkowski, D. J., Kaelin, W. G., Signoretti, S., & DePinho, R. A. (2010). FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis. Cancer cell, 18(5), 472-484. https://doi.org/10.1016/j.ccr.2010.10.019

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, Wang, YA, Kwiatkowski, DJ, Kaelin, WG, Signoretti, S & DePinho, RA 2010, 'FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis', Cancer cell, vol. 18, no. 5, pp. 472-484. https://doi.org/10.1016/j.ccr.2010.10.019

@article{18e95614aa2e475bb82fa739907e5a97,

title = "FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis",

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.",

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

note = "Funding Information: We are grateful to Anton Berns for providing Rosa26-CreERT2 mouse strain. We are also grateful to Shan (Julia) Zhou for the assistance in the animal facility. This research is supported by National Cancer Institute grant R21CA135057 (R.A.D., B.G.), U01CA141508 (R.A.D.), 1P01CA120964 (D.J.K.), DF/HCC Kidney Cancer SPORE Career Development Grant (P50CA101942-06A1) and DOD TSCRP Career Transition Award (TS093049) (B.G.). B.G. is the Research Fellow of the Leukemia and Lymphoma Society. S.H. is supported by Damon Runyon Cancer Research Foundation Postdoctoral Fellowship. Y.A.W. is supported by Multiple Myeloma Research Foundation. R.A.D. was supported by an American Cancer Society Research Professorship and the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. ",

year = "2010",

month = nov,

day = "16",

doi = "10.1016/j.ccr.2010.10.019",

language = "English (US)",

volume = "18",

pages = "472--484",

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T1 - FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis

AU - Gan, Boyi

AU - Lim, Carol

AU - Chu, Gerald

AU - Hua, Sujun

AU - Ding, Zhihu

AU - Collins, Michael

AU - Hu, Jian

AU - Jiang, Shan

AU - Fletcher-Sananikone, Eliot

AU - Zhuang, Li

AU - Chang, Michelle

AU - Zheng, Hongwu

AU - Wang, Y. Alan

AU - Kwiatkowski, David J.

AU - Kaelin, William G.

AU - Signoretti, Sabina

AU - DePinho, Ronald A.

N1 - Funding Information: We are grateful to Anton Berns for providing Rosa26-CreERT2 mouse strain. We are also grateful to Shan (Julia) Zhou for the assistance in the animal facility. This research is supported by National Cancer Institute grant R21CA135057 (R.A.D., B.G.), U01CA141508 (R.A.D.), 1P01CA120964 (D.J.K.), DF/HCC Kidney Cancer SPORE Career Development Grant (P50CA101942-06A1) and DOD TSCRP Career Transition Award (TS093049) (B.G.). B.G. is the Research Fellow of the Leukemia and Lymphoma Society. S.H. is supported by Damon Runyon Cancer Research Foundation Postdoctoral Fellowship. Y.A.W. is supported by Multiple Myeloma Research Foundation. R.A.D. was supported by an American Cancer Society Research Professorship and the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science.

PY - 2010/11/16

Y1 - 2010/11/16

N2 - 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.

AB - 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.

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DO - 10.1016/j.ccr.2010.10.019

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SP - 472

EP - 484

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

FoxOs enforce a progression checkpoint to constrain mTORC1-Activated renal tumorigenesis

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