Placental autophagy regulation by the BOK-MCL1 rheostat
| العنوان: | Placental autophagy regulation by the BOK-MCL1 rheostat |
|---|---|
| المؤلفون: | Megan Melland-Smith, Tullia Todros, Martin Post, Isabella Caniggia, Julia Garcia, Manpreet Kalkat, Jessica Ebrahimi |
| المصدر: | Autophagy. 9:2140-2153 |
| بيانات النشر: | Informa UK Limited, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Adult, Translational Research Paper, Programmed cell death, Placenta, Repressor, Biology, BAG3, BOK, Pre-Eclampsia, Downregulation and upregulation, Pregnancy, Autophagy, Homeostasis, Humans, oxidative stress, MCL1, RNA, Small Interfering, Molecular Biology, Cells, Cultured, MCL-1, Preeclampsia, HEK 293 cells, Cell Biology, BECN1, Cell biology, HEK293 Cells, Gene Expression Regulation, Proto-Oncogene Proteins c-bcl-2, Case-Control Studies, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Female |
| الوصف: | Autophagy is the catabolic degradation of cellular cytoplasmic constituents via the lysosomal pathway that physiologically elicits a primarily cytoprotective function, but can rapidly be upregulated in response to stressors thereby inducing cell death. We have reported that the balance between the BCL2 family proteins BOK and MCL1 regulates human trophoblast cell fate and its alteration toward cell death typifies preeclampsia. Here we demonstrate that BOK is a potent inducer of autophagy as shown by increased LC3B-II production, autophagosomal formation and lysosomal activation in HEK 293. In contrast, using JEG3 cells we showed that prosurvival MCL1 acts as a repressor of autophagy via an interaction with BECN1, which is abrogated by BOK. We found that MCL1-cleaved products, specifically MCL1c157, trigger autophagy while the splicing variant MCL1S has no effect. Treatment of JEG3 cells with nitric oxide donor SNP resulted in BOK-MCL1 rheostat dysregulation, favoring BOK accumulation, thereby inducing autophagy. Overexpression of MCL1 rescued oxidative stress-induced autophagy. Of clinical relevance, we report aberrant autophagy levels in the preeclamptic placenta due to impaired recruitment of BECN1 to MCL1. Our data provided the first evidence for a key role of the BOK-MCL1 system in regulating autophagy in the human placenta, whereby an adverse environment as seen in preeclampsia tilts the BOK-MCL1 balance toward the build-up of isoforms that triggers placental autophagy. |
| تدمد: | 1554-8635 1554-8627 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f73724985cc33d9c52598cbebd1247fcTest https://doi.org/10.4161/auto.26452Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f73724985cc33d9c52598cbebd1247fc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548635 15548627 |
|---|