Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Gauster, M; Maninger, S; Siwetz, M; Deutsch, A; El-Heliebi, A; Kolb-Lenz, D; Hiden, U; Desoye, G; Herse, F; Prokesch, A.
Downregulation of p53 drives autophagy during human trophoblast differentiation.
Cell Mol Life Sci. 2018; 75(10):1839-1855
Doi: 10.1007/s00018-017-2695-6
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- Führende Autor*innen der Med Uni Graz
- Gauster Martin
- Prokesch Andreas
- Co-Autor*innen der Med Uni Graz
- Desoye Gernot
- Deutsch Alexander
- El-Heliebi Amin
- Hiden Ursula
- Kolb Dagmar
- Maninger Sabine Elfriede
- Siwetz Monika
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- Abstract:
- The placental barrier is crucial for the supply of nutrients and oxygen to the developing fetus and is maintained by differentiation and fusion of mononucleated cytotrophoblasts into the syncytiotrophoblast, a process only partially understood. Here transcriptome and pathway analyses during differentiation and fusion of cultured trophoblasts yielded p53 signaling as negative upstream regulator and indicated an upregulation of autophagy-related genes. We further showed p53 mRNA and protein levels decreased during trophoblast differentiation. Reciprocally, autophagic flux increased and cytoplasmic LC3B-GFP puncta became more abundant, indicating enhanced autophagic activity. In line, in human first trimester placenta p53 protein mainly localized to the cytotrophoblast, while autophagy marker LC3B as well as late autophagic compartments were predominantly detectable in the syncytiotrophoblast. Importantly, ectopic overexpression of p53 reduced levels of LC3B-II, supporting a negative regulatory role on autophagy in differentiating trophoblasts. This was also shown in primary trophoblasts and human first trimester placental explants, where pharmacological stabilization of p53 decreased LC3B-II levels. In summary our data suggest that differentiation-dependent downregulation of p53 is a prerequisite for activating autophagy in the syncytiotrophoblast.
- Find related publications in this database (Keywords)
- Pregnancy
- Placenta
- Development
- Trophoblast fusion