Abstract
Conserved elements of apoptosis are also integral components of cellular differentiation. In this regard, p53 is involved in neurogenesis, being required for neurite outgrowth in primary neurons and for axonal regeneration in mice. Interestingly, demethylases regulate p53 activity and its interaction with co-activators by acting on non-histone proteins. In addition, the histone H3 lysine 27-specific demethylase JMJD3 induces ARF expression, thereby stabilizing p53 in mouse embryonic fibroblasts. We hypothesized that p53 interacts with key regulators of neurogenesis to redirect stem cells to differentiation, as an alternative to cell death. Specifically, we investigated the potential cross-talk between p53 and JMJD3 during mouse neural stem cell (NSC) differentiation. Our results demonstrated that JMJD3 mRNA and protein levels were increased early in mouse NSC differentiation, when JMJD3 activity was readily detected. Importantly, modulation of JMJD3 in NSCs resulted in changes of total p53 protein, coincident with increased ARF mRNA and protein expression. ChIP analysis revealed that JMJD3 was present at the promoter and exon 1 regions of ARF during neural differentiation, although without changes in H3K27me3. Immunoprecipitation assays demonstrated a direct interaction between p53 and JMJD3, independent of the C-terminal region of JMJD3, and modulation of p53 methylation by JMJD3-demethylase activity. Finally, transfection of mutant JMJD3 showed that the demethylase activity of JMJD3 was crucial in regulating p53 cellular distribution and function. In conclusion, JMJD3 induces p53 stabilization in mouse NSCs through ARF-dependent mechanisms, directly interacts with p53 and, importantly, causes nuclear accumulation of p53. This suggests that JMJD3 and p53 act in a common pathway during neurogenesis.
Highlights
It has been shown that components of the apoptosis process are pivotal for differentiation [1]
We have recently reported the involvement of specific apoptosis-related proteins in mouse neural stem cell (NSC) differentiation [2]. p53 phosphorylation and transcriptional activation increase throughout differentiation of mouse NSCs, with no evidence of apoptosis
Our results showed that JMJD3 mRNA and protein levels significantly increased at 1 day of mouse NSC differentiation (p,0.05)
Summary
It has been shown that components of the apoptosis process are pivotal for differentiation [1]. We have recently reported the involvement of specific apoptosis-related proteins in mouse neural stem cell (NSC) differentiation [2]. The specific targets and cofactors of p53 during neurogenesis are still largely unknown Once identified, they might be strategically manipulated to increase neural fate, as an alternative to cell death, and improve the efficiency of stem cell production. It is possible that p53 may sense epigenetic changes that accompany reprogramming of cells to either differentiated or undifferentiated stages. In this respect, p53 could be upregulated by events that reverse the Polycomb group (PcG) silencing mechanism and/or interfere with members of the PcG machinery. Analysis of embryonic stem cells revealed aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some tumors [12]
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