p53 Interaction with JMJD3 Results in Its Nuclear Distribution during Mouse Neural Stem Cell Differentiation

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.

α-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1

“…In addition, direct binding of ␣-syn to the DNA could trigger local changes in chromatin conformation, facilitating the interaction of p53 with its REs. Another interesting possibility is that the interaction of ␣-syn with p53 could recruit additional repressor factors, including the histone deacetylase Sin3A, as recently reported to occur in other systems (40,54). We present additional evidence for p53-mediated repression of Notch transcription, because partial knockdown of endogenous p53 in ARH-NPCs restored Notch expression to basal levels in cells overexpressing ␣-syn.…”

“…p53 can recruit transcription factors and chromatin modifier proteins (39,40) or can directly bind to the REs, as reported for the activation of Notch1 transcription in epithelial cells (29).…”

Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program

“…It has been shown that T-box transcription factors recruit H3K27me3 demethylases to chromatin (Miller et al, 2008;Miller and Weinmann, 2009). Similarly, p53 by interacting with JMJD3 cooperates to control neurogenesis (Sola et al, 2011). Moreover, recent data have revealed that Smad2/3 and Smad1 Dahle et al, 2010;Kim et al, 2011), by interacting with JMJD3, recruit it to some loci.…”

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

“…33 JMJD3 can also enhance the nuclear localization of p53 and thus regulate its function. 34 Moreover, JMJD3 interacts with chromatin modifiers independent of its demethylase activity, to stimulate transcription. 30,35 However, whether JMJD3 can demethylate non-histone proteins has not been reported prior to this study.…”