The double life of MULE in preeclamptic and IUGR placentae.

Cell Death & Disease
Alessandro RolfoI Caniggia

Abstract

The E3 ubiquitin ligase MULE (Mcl-1 Ubiquitin Ligases E3) targets myeloid cell leukemia factor 1 (Mcl-1) and tumor suppressor p53 for proteasomal degradation. Although Mcl-1 and p53 have been implicated in trophoblast cell death in preeclampsia (PE) and intrauterine growth restriction (IUGR), the mechanisms regulating their expression in the human placenta remains elusive. Herein, we investigated MULE's involvement in regulating Mcl-1 and p53 degradation during normal and abnormal (PE, IUGR) placental development. MULE expression peaked at 5-7 weeks of gestation, when oxygen tension is low and inversely correlated with that of Mcl-1 and p53. MULE efficiently bound to Mcl-1 and p53 and regulated their ubiquitination during placental development. Exposure of first trimester villous explants to 3% O(2) resulted in elevated MULE expression compared with 20% O(2). Low-oxygen-induced MULE expression in JEG3 choriocarcinoma cells was abolished by hypoxia-inducible factor (HIF)-1α siRNA. MULE was overexpressed in both PE and IUGR placentae. In PE, MULE preferentially targeted p53 for degradation, allowing accumulation of pro-apoptotic Mcl-1 isoforms. In IUGR, however, MULE targeted pro-survival Mcl-1, allowing p53 to accumulate and exe...Continue Reading

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Citations

Dec 23, 2015·BioMed Research International·Fan WuYi Lin
Oct 12, 2013·Autophagy·Manpreet KalkatIsabella Caniggia
Oct 29, 2017·Cellular and Molecular Life Sciences : CMLS·Martin GausterAndreas Prokesch
May 10, 2017·Reproduction : the Official Journal of the Society for the Study of Fertility·Li TangWenming Xu
Mar 7, 2021·Cancers·Mengwu Pan, Christine Blattner
Apr 21, 2021·Minerva Obstetrics and Gynecology·Edward Araujo JúniorLuciano M Nardozza

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Methods Mentioned

BETA
ubiquitination
PCR
immunoprecipitation
transfection
Assay

Software Mentioned

Prism
MULE

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