The consequences of increased 4E-BP1 in polycystic kidney disease.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Apoptosis
/ drug effects
Cell Cycle Proteins
/ metabolism
Cell Proliferation
/ drug effects
Cells, Cultured
Epithelial Cells
/ metabolism
Female
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Male
Mice
NADH, NADPH Oxidoreductases
/ metabolism
Phosphorylation
Polycystic Kidney Diseases
/ metabolism
Polycystic Kidney, Autosomal Dominant
/ metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
/ metabolism
Rats
TRPP Cation Channels
/ metabolism
4E-BP1
apoptosis
mitochondrial proteins
polycystic kidney disease
proliferation
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
10
05
2019
revised:
28
08
2019
accepted:
25
09
2019
pubmed:
28
10
2019
medline:
24
6
2020
entrez:
25
10
2019
Statut:
ppublish
Résumé
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, characterized by cyst formation and growth. Hyperproliferation is a major contributor to cyst growth. At the nexus of regulating proliferation, is 4E-BP1. We demonstrate that ADPKD mouse and rat models, ADPKD patient renal biopsies and PKD1-/- cells exhibited hyperphosphorylated 4E-BP1, a biomarker of increased translation and proliferation. We hypothesized that expression of constitutively active 4E-BP1 constructs (4E-BP1F113A and 4E-BP1R13AF113A) would decrease proliferation and reduce cyst expansion. Utilizing the Pkd1RC/RC mouse, we determined the effect of 4E-BP1F113A on PKD. Unexpectedly, 4E-BP1F113A resulted in increased cyst burden and suppressed apoptosis markers, increased anti-apoptotic Bcl-2 protein and increased mitochondrial proteins. Exogenous 4E-BP1 enhanced proliferation, decreased apoptosis, increased anti-apoptotic Bcl-2 protein, impaired NADPH oxidoreductase activity, increased mitochondrial proteins and increased superoxide production in PKD patient-derived renal epithelial cells. Reduced 4E-BP1 expression suppressed proliferation, restored apoptosis and improved cellular metabolism. These findings provide insight into how cyst-lining cells respond to 4E-BP1.
Identifiants
pubmed: 31646342
pii: 5599709
doi: 10.1093/hmg/ddz244
pmc: PMC7968387
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
EIF4EBP1 protein, human
0
Eif4ebp1 protein, mouse
0
Eif4ebp1 protein, rat
0
Intracellular Signaling Peptides and Proteins
0
PDK1 protein, human
0
Pdk1 protein, mouse
0
Pdk1 protein, rat
0
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
0
TRPP Cation Channels
0
NADH, NADPH Oxidoreductases
EC 1.6.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4132-4147Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK090868
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048154
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS086839
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007635
Pays : United States
Organisme : BLRD VA
ID : I01 BX003803
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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