Downregulation of p53 drives autophagy during human trophoblast differentiation

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.

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

“…To obtain a global view on functional changes during villous trophoblast differentiation, we analyzed the biological processes enriched among differentially expressed genes by DAVID (Table S4) and visualized their network by using the BiNGO [98] plugin in Cytoscape. As a good confirmation of our analysis, many of the most enriched biological processes ( Figure 3a) have been delineated by earlier studies on villous trophoblast differentiation [5,6,99]. There is a wide range of enriched biological processes (n = 952) related to the morphological and functional transformation from a proliferative cytotrophoblast into a metabolically and hormonally active end-differentiated syncytiotrophoblast, including 'programmed cell death', 'tissue development', 'apoptotic process', and 'cell cycle' as top enriched GO biological processes among differentially expressed (DE) genes (Table S4).…”

Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1

“…BRCA1 immunostaining within the ST was weaker and restricted to a few nuclei. A similar distribution pattern, i.e., absence or weak expression in ST versus high expression on vCTs and EVTs, has been described for several other cell cycle regulators including Ki67, cyclin A, p53, and p57 [24,43]. Considering that ST is characterized by the absence of an active cell cycle [44], BRCA1 positive nuclei within the ST might be the result of recent vCT-ST fusion.…”

cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53

“…However, a simplistic view on the association between p53 levels and autophagy was challenged by the notion that even more autophagy was detected concomitant with reduced levels of p53 when the BCP-ALL cells were co-exposed to irradiation and activators of the cAMP signaling pathway. Although reports have suggested that lowering the levels of p53 may facilitate autophagy [ 42 , 43 ], the consensus has been that the subcellular localization of p53 dictates its role in autophagy. Thus, induction of nuclear p53 is assumed to promote autophagy, whereas p53 in the cytosol protects the cells from autophagy [ 20 , 21 , 33 ].…”