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Mutated TP53 activates TP53. 50 / 50
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"These results support the hypothesis that TP53 mutations play a role in the late stage of tumorigenesis, such as progression step of adenomas to invasive adenocarcinomas or metastasis to distant organs.Cellular stress, like DNA damage, telomere erosion, hypoxia, and nutrient depletion, as well as oncogenic signaling, activates p53, leading to the promotion of cell-cycle arrest, senescence, and apoptosis depending on the extent and context of the stress (Vousden and Lu, 2002; Vousden and Prives, 2009)."
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"Recent studies have reported that TP53 mutations can modulate the function of p53 in the context of various cellular process, such as antioxidant defense and ferroptosis [8]."
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"The tumor suppressor protein p53 is inactivated by mutations of the TP53 gene in over 50% of human primary cancers [1,2]."
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"In many human cancers, p53 dysfunction, often caused by TP53 mutations or signaling pathway disruptions, is observed [1]."
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"TP53 mutations may increase the half-life of the p53 protein product and immunohistochemical staining for p53 has been proposed as a surrogate marker."
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"The high frequency of TP53 mutations in breast tumors also enables the extensive application of p53-targeted therapies [48]."
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"Moreover, experimental evidence demonstrates that some nondisruptive TP53 mutations induce "gain of function" (GOF) activities, rather than resulting in simple loss of function of wt p53."
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"These findings suggest that p53 dysfunction caused by TP53 mutations leads to tumor progression and impaired outcomes for AML."
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"In light of these observations, it is not surprising that the loss of p53 wild-type activity caused by most TP53 mutations results in a deregulated tumor cell secretome impacting on the reciprocal crosstalk of tumor cells with the plethora of cell types in their microenvironment."
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"For example, TP53 mutations lead to the production of a mutant dysfunctional p53 protein that is significantly more stable and long-lived than wild-type (wt) p53, which is rapidly degraded by the ubiquitin–proteasome system [7,11]."
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"The high, but not perfect, sensitivity was influenced by non‐functional p53 proteins caused by late truncating TP53 mutations that showed normal wild type pattern by IHC [3]."
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"Over-expression of the dominant negative p53 mutant DeltaTAp53, which inhibits p53 activity, prevented the TPA induced K14 down-regulation in C9 cells."
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"EOC cells are presumably vulnerable to the inhibition of S- and G /M-phase DNA damage checkpoints, owing to the aberrant p53 signaling caused by TP53 mutation, the predominant genetic alteration in human EOC that abrogates the G checkpoint and renders EOC cells more dependent on S- and G /M-phase DNA damage checkpoints (15)."
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"Cells carrying a TP53 mutation accumulate high levels of mutant p53 protein, which drives a dominant-negative effect on the wild-type (WT) copy and the p53 homologs p63 and p73 (3)."
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"TP53 mutation induces a precursor phenotype called the p53 signature, containing a loss of ciliated cells, and an outgrowth of secretory cells with DNA damage accumulation ."
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"Simulated expression profiles suggest that in cells harboring p53 hotspot mutations, the constant high levels of mutant p53 can preferentially induce the expression of pro-survival targets with residu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"However, it was found that the expression of a dominant-negative mutant p53 which inactivates p53 by forming non-functional tetramers, reduced rather than increased CCEPR expression."
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"EZH2 augmented p53 GOF mutant mediated cancer growth and metastasis by increasing protein levels of mutant p53."
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"The overexpression of mutant p53 stimulates serum p53 antibody production in patients with colorectal carcinoma even in superficial tumors."
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"More significantly, Ser20 phosphorylation of specific p53 mutants with oxali-Pt also activates p53 function, and this raises the likelihood that other p53 mutants in refractory human ovarian cancers could also be functionally activated with distinct drugs, such as oxali-Pt, to restore therapeutic sensitivity."
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"Nevertheless, in TP53 mutant cells, SURF2 depletion still negatively impacts cancer cells, suggesting that in addition to promoting p53 activation, SURF2 also induces p53-independent negative effects."
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"These ' gain-of-function ' (GOF) TP53 mutations cause mutp53 to accumulate at high levels in cells, contributing to tumorigenesis and the development of drug resistance XREF_BIBR."
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"This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions."
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"Some discrepancies in these results could be explained by the existence of different TP53 mutations which can differently modulate p53 accumulation in the cell nuclei."
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"Further supporting these data, we show that acetylation-mimicking mutation of p53 results in a decrease in S367p, which could, in fact, be an indispensable event for enhancing the stability of p53, increasing the recruitment of p53 to target genes, and activating the transcriptional function of p53 upon DNA damage."
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"The inactivation of the p53 protein induced by TP53 mutations is considered to be the initiator of the genomic instability, cell-cycle activation, and malignant biological behaviors of UC.1 2 In our previous study, TP53 disruptive mutation, causing p53 protein loss of function, was found to be associated with poor prognosis and invasive subtype transformation in patients with UC."
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"A p53-mutant protein fails to transcribe the MDM2 gene and in the absence of an MDM2 protein the mutant p53 protein levels increase up to ten fold more p53 protein compared with cells with WT p53."
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"33 Since the KELLY and BE(2)‐C cell lines possess TP53 mutations which increase the stability of p53 protein, 34 , 35 we assessed whether the reduction in protein levels could be attributed to loss of protein stability using cycloheximide chase (CHX) assays."
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"YD-15 cells were selected for the study of mutant p53 function restoration.A treatment strategy for carcinoma with the TP53 mutation is restoring the p53 function (9)."
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"TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer."
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"TP53 mutations produce altered p53, which is nonfunctional and can also exert a dominant-negative effect on the residual WT-p53."
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"While all cancer-relevant TP53 mutations probably abolish the tumor suppressive effects of wild-type p53, missense, but not null mutations, may potentially confer gain-of-function activities [14,15]."
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"Non-disruptive TP53 mutations, which cause partial loss of p53 function having a retained functional property associated with gain of function (GOF) representing a heterogenous subgroup of ALK rearranged NSCLC patients with inferior PFS [47]."
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"As expected, mutant p53 expressed in SKNBe2C and SKNAS cells remained unaffected by MDM2-p53 antagonist treatment, but induced p53 stabilisation in p53 wt SHSY5Y cells (XREF_FIG)."
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"Most but not all TP53 mutations causes accumulation of p53 in the cell nuclei."
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"These findings should be kept on the horizon and studied on a larger scale to determine whether or not this is clinically significant and whether patients acquire de novo TP53 mutations with idasanutlin treatment.There are also early phase trials ongoing evaluating APR-246 (eprenetapopt), a small molecule that restores wild-type p53 functions in TP53-mutant cells."
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"TP53 is a well-known tumor-suppressor, while the p53 inactivation caused by TP53 mutations can escape tumor cell death and rapid tumor progression [50]."
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"Somewhat surprisingly, we found that expression of a dominant negative TP53 mutant that inactivates TP53 by forming non functional tetramers (Gottlieb et al., 1994), decreased rather than increased CC[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Remarkably, p53-mediated transcriptional suppression of SLC7A11 contributes to ferroptosis in cancer cells (58), and mutations of TP53 modulate the ability of p53 to promote apoptosis and ferroptosis (59)."
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"Although in various cancers increased nuclear p53 accumulation is frequently caused by TP53 mutations ( Greenblatt et al., 1994 ), we could not detect any mutations in the most commonly affected exons[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Overall, the p53 pathway mutations, mostly contributed by TP53 mutations (Supplementary Figure S5C) were negatively correlated with CDKN2A homozygous deletion and positively correlated with both CDK4 amplification and RB1 inactivation (Figure 4h, Supplementary Figure S5B)."
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"Unlike wt p53, mutant p53 is normally expressed at high levels in tumor cells, most likely due to the inability to induce components of p53 negative-feedback loops such as MDM2, Cop1, or Pirh2."
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"Almost all tumor cells deactivate p53, most of which is mediated by TP53 mutations[171]."
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"These data indicate that ectopic expression of wild-type p53 can repress dUTPase promoter activity and that ectopic p53 mutant expression can induce dUTPase promoter activity in the HCT116 p53 isogenic cell-line models."
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"5 In contrast to the majority of other tumor suppressors, TP53 mutations are usually missense and produce full-length p53 protein with an increased half-life."
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"P53 tumor suppressor protein is involved in the regulation of centrosome duplication : loss of p53 as well as expression of certain p53 mutants result in deregulated centrosome duplication and centrosome amplification."
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"TP53 mutations suppress the transcriptional activity of the wild-type p53 tumor suppressor and have been associated with advanced disease stages and a poor prognosis."
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"Expression of an acetylation-resistant (K120R) p53 mutant or lentivirus-mediated suppression of KAT8 and Tip60 reduces the ability of p53 to induce Bax and Puma in cells in vitro ."
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"In this scenario, it is not surprising that the alterations of p53 activity caused by different TP53 mutations can result in a dysregulated senescence and tumor secretome, affecting the complex crosstalk between tumor cells and a plethora of cell types in the surrounding stromal microenvironment."
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"The first such mechanism discovered showed that mutant p53 proteins abrogate the tumor-suppressive activities of the p53 family members p63 and p73."
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