PUBLICATION

TRIM28 regulates sprouting angiogenesis through VEGFR-DLL4-Notch signaling circuit

Authors
Yang, Yinfang, Singh, Angom Ramcharan, Zhao, Yuanyuan, Du, Tao, Huang, Yitong, Wan, Xiaohong, Mukhopadhyay, Debabrata, Wang, Ying, Wang, Nanping, Zhang, Peng
ID
ZDB-PUB-200930-1
Date
2020
Source
FASEB journal : official publication of the Federation of American Societies for Experimental Biology   34(11): 14710-14724 (Journal)
Registered Authors
Mukhopadhyay, Debabrata
Keywords
none
MeSH Terms
  • p38 Mitogen-Activated Protein Kinases/metabolism
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Receptors, Vascular Endothelial Growth Factor/genetics
  • Receptors, Vascular Endothelial Growth Factor/metabolism
  • Hypoxia-Inducible Factor 1/metabolism
  • Neovascularization, Physiologic*
  • Animals
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism
  • Tripartite Motif-Containing Protein 28/genetics
  • Tripartite Motif-Containing Protein 28/metabolism*
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Male
  • Humans
  • Rats
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction*
PubMed
32918765 Full text @ FASEB J.
Abstract
Sprouting angiogenesis is a highly coordinately process controlled by vascular endothelial growth factor receptor (VEGFR)?Notch signaling. Here we investigated whether Tripartite motif?containing 28 (TRIM28), which is an epigenetic modifier implicated in gene transcription and cell differentiation, is essential to mediate sprouting angiogenesis. We observed that knockdown of TRIM28 ortholog in zebrafish resulted in developmental vascular defect with disorganized and reduced vasculatures. Consistently, TRIM28 knockdown inhibited angiogenic sprouting of cultured endothelial cells (ECs), which exhibited increased mRNA levels of VEGFR1, Delta?like (DLL) 3, and Notch2 but reduced levels of VEGFR2, DLL1, DLL4, Notch1, Notch3, and Notch4.The regulative effects of TRIM28 on these angiogenic factors were partially mediated by hypoxia?inducible factor 1 ? (HIF?1?) and recombination signal?binding protein for immunoglobulin kappa J region (RBPJ?). In vitro DNA?binding assay showed that TRIM28 knockdown increased the association of RBPJ? with DNA sequences containing HIF?1??binding sites. Moreover, the phosphorylation of TRIM28 was controlled by VEGF and Notch1 through a mechanism involving RBPJ??dual?specificity phosphatase (DUSP)?p38 MAPK, indicating a negative feedback mechanism. These findings established TRIM28 as a crucial regulator of VEGFR?Notch signaling circuit through HIF?1? and RBPJ? in EC sprouting angiogenesis.
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