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% O2 resulted in elevated MULE expression compared with 20% O2. 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 exert its apoptotic function. These data demonstrate that oxygen regulates Mcl-1 and p53 stability during placentation via HIF-1-controlled MULE expression. The different preferential targets of MULE in PE and IUGR placentae classify early-onset PE and IUGR as distinct molecular pathologies.
Highlights
5–10% of all pregnancies, respectively, and are one of the leading causes of fetal and maternal mortality and morbidity.[1,2] PE manifests itself with a wide variety of maternal symptoms including hypertension and proteinuria,[3] whereas
MULE association to myeloid cell leukemia factor 1 (Mcl-1) was maximal at 5–6 weeks (Figure 1c, right panel) and Mcl-1 ubiquitination peaked at 7–9 weeks (Figure 1c, left panel): at the time when Mcl-1 levels are low (Figure 1b, bottom left panel)
As hypoxia-inducible factor (HIF)-1a is a major player in the physiological response to hypoxia, we examined HIF-1a protein expression during placental development and found that it paralleled that of MULE (Figure 1b, left panel), showing a peak of expression at 5–7 weeks that decreases with advancing gestation (Figure 3b, right upper panel)
Summary
5–10% of all pregnancies, respectively, and are one of the leading causes of fetal and maternal mortality and morbidity.[1,2] PE manifests itself with a wide variety of maternal symptoms including hypertension and proteinuria,[3] whereas. IUGR may be caused by a variety of conditions such as infections, maternal diseases and chromosomal disorders, but more often, as in PE, its genesis is related to a defect in proper placental development originating early in pregnancy Typical features of both severe IUGR and PE are altered trophoblast cell proliferation and reduced chorionic vessel development, leading to impaired angiogenesis.[8]. Bcl-2 family proteins form a complex network of cell death inducers and suppressors that via their interactions determine cell fate.[13] Bcl-2 pro-apoptotic proteins act mainly by localizing permanently or transiently to the outer mitochondrial membrane where they regulate or form pores. Beside MULE, p53 protein stability is regulated by two other well-characterized ubiquitin ligases, such as murine double minute-2 (Mdm2) and murine double minute-X (MdmX).[21,22] Expression of p53 is elevated in placentae from pregnancies complicated by IUGR.[9,12] As placental pathologies, including PE and IUGR, are characterized by altered expression of key regulators of trophoblast cell fate such as Mcl-1 and p53, we hypothesized that changes in MULE expression and activity may contribute to the altered balance in pro-survival and death-inducing molecules typical of these pathologies
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