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TFEB controls vascular development by regulating the proliferation of endothelial cells
Author(s) -
Doronzo Gabriella,
Astanina Elena,
Corà Davide,
Chiabotto Giulia,
Comunanza Valentina,
Noghero Alessio,
Neri Francesco,
Puliafito Alberto,
Primo Luca,
Spampanato Carmine,
Settembre Carmine,
Ballabio Andrea,
Camussi Giovanni,
Oliviero Salvatore,
Bussolino Federico
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798250
Subject(s) - cancer , medicine , library science , oncology , cancer research , computer science
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/ VEGFR 2 pathway in the developing vasculature. In endothelial cells, TFEB depletion halts proliferation at the G1‐S transition by inhibiting the CDK 4/Rb pathway. TFEB ‐deficient cells attempt to compensate for this limitation by increasing VEGFR 2 levels at the plasma membrane via micro RNA ‐mediated mechanisms and controlled membrane trafficking. TFEB stimulates expression of the miR‐15a/16‐1 cluster, which limits VEGFR 2 transcript stability and negatively modulates expression of MYO 1C, a regulator of VEGFR 2 trafficking to the cell surface. Altered levels of miR‐15a/16‐1 and MYO 1C in TFEB ‐depleted cells cause increased expression of plasma membrane VEGFR 2, 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 VEGFR 2 pathway. These previously unrecognized functions of TFEB expand its role beyond regulation of the autophagic pathway in the vascular system.