title: ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway.
abstract: Renal compensatory hypertrophy (RCH) restores normal kidney function after disease or loss of kidney tissue and is characterized by an increase in organ size due to cell enlargement and not to cell proliferation. In MDCK renal epithelial cells, silencing of the tight junction protein zona occludens 2 (ZO-2 KD) induces cell hypertrophy by two mechanisms: prolonging the time that cells spend at the G1 phase of the cell cycle due to an increase in cyclin D1 level, and augmenting the rate of protein synthesis. The latter is triggered by the nuclear accumulation and increased transcriptional activity of Yes-associated protein (YAP), the main target of the Hippo pathway, which results in decreased expression of phosphatase and tensin homologue. This in turn increased the level of phosphatidylinositol (3,4,5)-triphosphate, which transactivates the Akt/mammalian target of rapamycin pathway, leading to activation of the kinase S6K1 and increased synthesis of proteins and cell size. In agreement, in a rat model of uninephrectomy, RCH is accompanied by decreased expression of ZO-2 and nuclear expression of YAP. Our results reveal a novel role of ZO-2 as a modulator of cell size.
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Alaide
authors.initials: A
authors.lastname: Domínguez-Calderón
authors.affiliation: Department of Immunology and Oncology, National Center of Biotechnology/CSIC, Darwin 3 UAM, E-28049 Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ávila-Flores
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Arturo
authors.initials: A
authors.lastname: Ponce
authors.affiliation: Department of Toxicology, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Esther
authors.initials: E
authors.lastname: López-Bayghen
authors.affiliation: Department of Biochemistry, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: José-Víctor
authors.initials: JV
authors.lastname: Calderón-Salinas
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: José
authors.initials: J
authors.lastname: Luis Reyes
authors.affiliation: Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Chávez-Munguía
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: José
authors.initials: J
authors.lastname: Segovia
authors.affiliation: Department of Toxicology, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Carla
authors.initials: C
authors.lastname: Angulo
authors.affiliation: Department of Toxicology, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Leticia
authors.initials: L
authors.lastname: Ramírez
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Helios
authors.initials: H
authors.lastname: Gallego-Gutiérrez
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Alarcón
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Dolores
authors.initials: D
authors.lastname: Martín-Tapia
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México.
authors.forename: Pablo
authors.initials: P
authors.lastname: Bautista-García
authors.affiliation: Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México lorenza.goma@gmail.com.
authors.forename: Lorenza
authors.initials: L
authors.lastname: González-Mariscal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects; D049109:Cell Proliferation / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D004285:Dogs; D016193:G1 Phase / Q000502:physiology; D006984:Hypertrophy; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D062827:Zonula Occludens-2 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D062827:Zonula Occludens-2 Protein; D019938:Cyclin D1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat