TFEB controls vascular development by regulating the proliferation of endothelial cells.
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ physiology
Cell Proliferation
Cells, Cultured
Embryo, Mammalian
/ cytology
Endothelium, Vascular
/ cytology
Female
Gene Expression Regulation, Developmental
Mice
Mice, Inbred C57BL
Mice, Knockout
Neovascularization, Physiologic
Signal Transduction
Vascular Endothelial Growth Factor Receptor-2
/ genetics
angiogenesis
embryo
membrane trafficking
miRNA transcription
proliferation
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
18
09
2017
revised:
12
11
2018
accepted:
20
11
2018
pubmed:
29
12
2018
medline:
7
1
2020
entrez:
29
12
2018
Statut:
ppublish
Résumé
Transcription factor TFEB is thought to control cellular functions-including in the vascular bed-primarily via regulation of lysosomal biogenesis and autophagic flux. Here, we report that TFEB also orchestrates a non-canonical program that controls the cell cycle/VEGFR2 pathway in the developing vasculature. In endothelial cells, TFEB depletion halts proliferation at the G1-S transition by inhibiting the CDK4/Rb pathway. TFEB-deficient cells attempt to compensate for this limitation by increasing VEGFR2 levels at the plasma membrane via microRNA-mediated mechanisms and controlled membrane trafficking. TFEB stimulates expression of the miR-15a/16-1 cluster, which limits VEGFR2 transcript stability and negatively modulates expression of MYO1C, a regulator of VEGFR2 trafficking to the cell surface. Altered levels of miR-15a/16-1 and MYO1C in TFEB-depleted cells cause increased expression of plasma membrane VEGFR2, but in a manner associated with low signaling strength. An endothelium-specific Tfeb-knockout mouse model displays defects in fetal and newborn mouse vasculature caused by reduced endothelial proliferation and by anomalous function of the VEGFR2 pathway. These previously unrecognized functions of TFEB expand its role beyond regulation of the autophagic pathway in the vascular system.
Identifiants
pubmed: 30591554
pii: embj.201798250
doi: 10.15252/embj.201798250
pmc: PMC6356157
pii:
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Tcfeb protein, mouse
0
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 694282
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS078072
Pays : United States
Informations de copyright
© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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