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TRIM28 regulates sprouting angiogenesis through VEGFR‐DLL4‐Notch signaling circuit
Author(s) -
Wang Yinfang,
Singh Angom Ramcharan,
Zhao Yuanyuan,
Du Tao,
Huang Yitong,
Wan Xiaohong,
Mukhopadhyay Debabrata,
Wang Ying,
Wang Nanping,
Zhang Peng
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000186rrr
Subject(s) - notch signaling pathway , angiogenesis , microbiology and biotechnology , gene knockdown , biology , sprouting angiogenesis , transcription factor , signal transduction , cancer research , chemistry , neovascularization , gene , genetics
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 α (HIF‐1α) and recombination signal‐binding protein for immunoglobulin kappa J region (RBPJκ). In vitro DNA‐binding assay showed that TRIM28 knockdown increased the association of RBPJκ with DNA sequences containing HIF‐1α‐binding sites. Moreover, the phosphorylation of TRIM28 was controlled by VEGF and Notch1 through a mechanism involving RBPJκ‐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‐1α and RBPJκ in EC sprouting angiogenesis.