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ATXN3 activates TP53. 16 / 22
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"Activation of p53 by mutant ataxin-3 is also related to phosphorylation of p53 at ser15 residue in the SCA3 transgenic mice model."
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"In cell and animal models of SCA3 induced by ataxin-3 mutation, mutant SCA3 can induce apoptosis of cerebellum and pons neurons by enhancing p53 transcriptional activity (Chou et al., 2011)."
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"These results suggest that ATX-3 deletion inhibits the stimulation of p53 transactivation activity."
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"Furthermore, to test whether mutant ATXN3 activates p53 and Chk2 via activating ATM, we pre-treated the cells with ATM inhibitor Ku55933 and expressed ATXN3-Q84 and assessed the activation of DNA damage response pathway."
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"These findings suggest that polyglutamine-expanded ataxin-3 enhances p53 transcriptional activity, which subsequently upregulates mRNA expression of pro-apoptotic Bax and PUMA.Mutant ataxin-3 enhancem[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"ATX-3 Promotes p53 Dependent Apoptosis in Cells and in Zebrafish."
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"Flow cytometry analysis using Annexin V-FITC and propidium iodide (PI) staining in HCT116 cells showed that knockdown of ATX-3 led to a decrease of camptothecin (CPT)-induced apoptosis, while ectopic expression of ATX-3 but not the catalytic inactive mutant ATX-3-C14A resulted in a significant increase of apoptosis in HCT116 p53 +/+ but not HCT116 p53 -/- cells (XREF_FIG), indicating that ATX-3 promoted p53 mediated apoptosis, which required its deubiquitinating enzymatic activity."
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"Using the zebrafish model system, we further examined whether ATX-3 induces p53 dependent apoptosis in vivo."
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"Deletion of ATXN3 resulted in destabilization of p53, whereas ectopic expression of ATXN3 induced expression of p53 target genes and promoted p53-dependent apoptosis."
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"When the FL ATX-3 mRNA was injected into WT but not the p53 mutant zebrafish embryos, significantly more apoptotic cells were observed in TUNEL staining assays, indicating that ATX-3 caused p53 dependent apoptosis in vivo."
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"Thus, it is very likely that instead of increasing p53 expression, polyglutamine-expanded ataxin-3 augments p53 transcriptional activity by promoting post-translational modification of p53."
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"Besides, we found that the degradation of p53 in the ATX-3 exp (80Q)-expressing cells was slower than that of normal ATX-3-expressing cells (XREF_SUPPLEMENTARY), and ectopic expression of polyQ expanded ATX-3 induced higher levels of p53 protein than the normal ATX-3 in RKO, 293T, and MEF cells (XREF_SUPPLEMENTARY), indicating that polyQ expanded ATX-3 possessed enhanced capability to stabilize p53."
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"The expression levels of p53 responsive genes (such as p21 and Puma) were also higher in ATX-3 exp (80Q) expressing RKO cells (XREF_SUPPLEMENTARY), suggesting that p53 was functionally enhanced by polyQ expansion in ATX-3."
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"ATXN3 and USP28 have been shown to activate TP53 signaling (Liu et al., 2016; Wang et al., 2018b), and knockouts of both of these genes positively correlated with TP53 knockout in DepMap data, supporting the hypothesis that these DUBs are positive regulators of TP53."
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"As P53 has known functions in cycle arrest and apoptosis, this indicates that expression of atxn3 polyQ repeats induces selective transcription and expression of p53 target genes and promotes p53 dependent apoptosis in the CNS of zebrafish [XREF_BIBR]."
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"However, the polyQ expanded ATX-3 induced progressive severe p53 dependent neurodegeneration in the central nervous system of zebrafish, suggesting that it caused other kinds of p53 mediated neural cell death besides apoptosis, too."
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