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.
authors.affiliation: Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA.
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Carol
authors.initials: C
authors.lastname: Lim
authors.forename: Gerald
authors.initials: G
authors.lastname: Chu
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Eliot
authors.initials: E
authors.lastname: Fletcher-Sananikone
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.forename: Michelle
authors.initials: M
authors.lastname: Chang
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation; D000077004:Tuberous Sclerosis Complex 1 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs; D046912:Multiprotein Complexes; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C543499:MIRN145a microRNA, mouse; C512788:Mxi1 protein, mouse; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse