PMID- 25288394
OWN - NLM
STAT- MEDLINE
DCOM- 20150219
LR  - 20220409
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 211
IP  - 11
DP  - 2014 Oct 20
TI  - Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous 
      sclerosis complex.
PG  - 2249-63
LID - 10.1084/jem.20140341 [doi]
AB  - Genetic studies have shown that the tuberous sclerosis complex (TSC) 
      1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 
      1 (YAP) pathways are master regulators of organ size, which are often involved in 
      tumorigenesis. The crosstalk between these signal transduction pathways in 
      coordinating environmental cues, such as nutritional status and mechanical 
      constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP 
      remains elusive. Here we describe a novel mouse model of TSC which develops renal 
      mesenchymal lesions recapitulating human perivascular epithelioid cell tumors 
      (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in 
      mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces 
      apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant 
      mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is 
      due to impaired degradation of the protein by the autophagosome/lysosome system. 
      Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth 
      control, matching YAP activity with nutrient availability under growth-permissive 
      conditions. YAP may serve as a potential therapeutic target for TSC and other 
      diseases with dysregulated mTOR activity.
CI  - (c) 2014 Liang et al.
FAU - Liang, Ning
AU  - Liang N
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Zhang, Chi
AU  - Zhang C
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Dill, Patricia
AU  - Dill P
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France Department of Pediatric 
      Neurology and Developmental Medicine, University Children's Hospital Basel, 
      University of Basel, 4056 Basel, Switzerland.
FAU - Panasyuk, Ganna
AU  - Panasyuk G
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Pion, Delphine
AU  - Pion D
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Koka, Vonda
AU  - Koka V
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Gallazzini, Morgan
AU  - Gallazzini M
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Olson, Eric N
AU  - Olson EN
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, TX 75390.
FAU - Lam, Hilaire
AU  - Lam H
AD  - Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Henske, Elizabeth P
AU  - Henske EP
AD  - Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Dong, Zheng
AU  - Dong Z
AD  - Department of Cellular Biology and Anatomy, Georgia Health Sciences University 
      and Charlie Norwood VA Medical Center, Augusta, Georgia, GA 30192.
FAU - Apte, Udayan
AU  - Apte U
AD  - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas 
      Medical Center, Kansas City, KS 66160.
FAU - Pallet, Nicolas
AU  - Pallet N
AD  - Institut National de la Sante et de la Recherche Medicale U775 and Universite 
      Paris Descartes, 75006 Paris, France Service de Nephrologie, Hopital Europeen 
      Georges Pompidou, F-75015 Paris, France.
FAU - Johnson, Randy L
AU  - Johnson RL
AD  - Department of Biochemistry and Molecular Biology, University of Texas MD Anderson 
      Cancer Center, Houston, Texas 77030.
FAU - Terzi, Fabiola
AU  - Terzi F
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
AD  - Translational Medicine Division, Department of Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Scoazec, Jean-Yves
AU  - Scoazec JY
AD  - Hospices Civils de Lyon, Hopital E. Herriot, 69437 Lyon, France.
FAU - Martignoni, Guido
AU  - Martignoni G
AD  - Department of Pathology and Diagnostic, University of Verona, 37129 Verona, Italy 
      Pederzoli Hospital, Peschiera, 37134 Verona, Italy.
FAU - Pende, Mario
AU  - Pende M
AD  - Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la 
      Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris 
      Descartes, Sorbonne Paris Cite, 75006 Paris, France mario.pende@inserm.fr.
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - R01 DK096556/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141006
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Porphyrins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yap1 protein, mouse)
RN  - 0X9PA28K43 (Verteporfin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Angiomyolipoma/genetics/metabolism
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - *Autophagy/drug effects/genetics
MH  - Cell Cycle Proteins
MH  - Cell Proliferation
MH  - Cell Survival/drug effects/genetics
MH  - Disease Models, Animal
MH  - Gene Expression Regulation
MH  - Humans
MH  - Immunohistochemistry
MH  - Kidney/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphoproteins/genetics/*metabolism
MH  - Porphyrins/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis/genetics/*metabolism/pathology
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/genetics/metabolism
MH  - Up-Regulation
MH  - Verteporfin
MH  - YAP-Signaling Proteins
PMC - PMC4203941
EDAT- 2014/10/08 06:00
MHDA- 2015/02/20 06:00
PMCR- 2015/04/20
CRDT- 2014/10/08 06:00
PHST- 2014/10/08 06:00 [entrez]
PHST- 2014/10/08 06:00 [pubmed]
PHST- 2015/02/20 06:00 [medline]
PHST- 2015/04/20 00:00 [pmc-release]
AID - jem.20140341 [pii]
AID - 20140341 [pii]
AID - 10.1084/jem.20140341 [doi]
PST - ppublish
SO  - J Exp Med. 2014 Oct 20;211(11):2249-63. doi: 10.1084/jem.20140341. Epub 2014 Oct 
      6.