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Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3276-81. doi: 10.1073/pnas.1008098108. Epub 2011 Feb 7.

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1.

Author information

1
Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.

Abstract

JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF-receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting.

PMID:
21300889
PMCID:
PMC3044381
DOI:
10.1073/pnas.1008098108
[Indexed for MEDLINE]
Free PMC Article

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