Jumonji Domain Containing Protein 6 Is Decreased in Human Preeclamptic Placentas and Regulates sFLT-1 Splice Variant Production

Biology of Reproduction
Kirsten PalmerTu'uhevaha J Kaitu'u-Lino

Abstract

The anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1), plays a central role in preeclamptic pathophysiology. A splice variant of FLT-1 (VEGF receptor 1), sFLT-1 is released in excessive amounts from the preeclamptic placenta into the maternal circulation, where it causes endothelial dysfunction manifesting as end-organ disease. However, the mechanisms regulating its production within the placenta remain poorly understood. Recently it was shown in endothelial cells that Jumonji domain containing protein 6 (JMJD6) hydroxylates U2 small nuclear ribonucleoprotein auxiliary factor 65-kDa subunit (U2AF65, a component of the splicesome). The hydroxylation by JMJD6 is oxygen dependent. Under hypoxia, JMJD6 is less able to hydroxylate U2AF65, and this unhydroxylated form of U2AF65 biases splicing of FLT-1 to sFLT-1. We assessed whether oxygen-sensing JMJD6 is differentially expressed in preeclamptic placenta and regulates sFLT-1 splicing in placenta via U2AF65. JMJD6 protein expression was significantly reduced in preterm preeclamptic placenta (P < 0.0001; n = 21) relative to preterm controls (n = 10). Exposing both placental and endothelial cells to hypoxia significantly reduced JMJD6 mRNA and increased sFLT-1 mRNA a...Continue Reading

References

Nov 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·R L Kendall, K A Thomas
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Apr 22, 2006·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Ori NevoIsabella Caniggia
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Aug 21, 2008·The Biochemical Journal·Patrick J PollardPeter J Ratcliffe
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Jun 4, 2015·Endocrinology·Sruthi AlahariIsabella Caniggia

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Citations

Aug 25, 2016·Oncotarget·Coralie PoulardMuriel Le Romancer
Sep 10, 2020·International Journal of Molecular Sciences·Takayuki IkedaHideto Yonekura
Jan 25, 2019·Scientific Reports·Cherine Abou FaycalBeatrice Eymin
Oct 16, 2018·Frontiers in Oncology·Giuseppe BiamontiAlessandra Montecucco
Jul 1, 2020·Biomolecules·Manoj Kumar JenaNihar Ranjan Nayak
Apr 30, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Sangphil OhRalf Janknecht

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