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TP53 activates TP53. 1000 / 1756
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"N-acetyl cysteine (NAC), superoxide dismutase, and catalase mimetic attenuate UVB induced p53 stabilization without altering the transcriptional activation and cell cycle arrest functions of p53, suggesting a role for oxidative stress in UVB induced p53 stabilization and accumulation."
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"The expression of the pro-apoptotic protein, Bax, was upregulated, while the expression of the anti-apoptotic protein, bcl-2, was down-regulated.The p53 protein is produced by the expression of the P53 gene on the short arm of chromosome 17 and is involved in the processes of apoptosis, aging, and DNA damage repair [32]."
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"LncRNA SCARNA10 promotes the interaction of p53 with CREB-binding proteins by binding to the DNA-binding domain of p53 and increasing the level of p53 acetylation, which activates p53-mediated transcriptional activation and enhances the sensitivity of tumor cells to ferroptosis (60).4
LncRNAs in ferroptosis of immune cells and tumor immunity."
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"Despite little evidence that p53 contributes to normal mammalian development, enforced p53 expression triggers differentiation in certain p53 deficient tumor cells and, conversely, p53 loss has been described as a factor that promotes de-differentiation during glioblastoma development in mice."
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"In contrast, a recent study found that the N protein virus bound to constitutively photomorphogenic 1 (COP1) via its N-terminal domain (1–124 aa) and inhibited COP1 degradation, thereby promoting the COP1-mediated ubiquitination and degradation of p53, abolishing the antiviral activity of p53 [66]."
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"Similarly, we found that RGS6 is required for urothelial BBN induced p53 activation and caspase 3 cleavage as the transient peak in p53 activation (phosphorylation of S15) and in caspase 3 cleavage in RGS6 +/+ mice at 2-3 days following BBN exposure was significantly blunted in RGS6 -/- mice."
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"SET has been shown to inhibit p53 acetylation and repress p53-mediated gene transcription, which also impairs p53-dependent apoptosis and enhances estrogen-dependent cell growth and survival.SET is frequently overexpressed in acute myeloid leukemia, head and neck squamous cell carcinoma, Wilms’ tumor, colorectal cancer, and human breast cancer and overexpression is associated with tumor progression and poor prognosis (6)."
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"MIA-PaCa-2 cells possess a R248W TP53 gain-of-function mutation resulting in expression of a p53 protein with a mutated DNA binding domain effectively blocking the tumour suppressive properties of p53 [120]; transfecting MIA-PaCa-2 cells to express wildtype p53 caused a three-fold reduction in the IC of BBR [121]."
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"PGAM1 activity has been reported to be upregulated in many cancers, including hepatocellular carcinoma and colorectal cancer XREF_BIBR, XREF_BIBR, probably due to increased PGAM1 gene expression resulting from loss of TP53, as PGAM1 is a negative transcription target of TP53 XREF_BIBR - XREF_BIBR."
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"These studies (mostly performed in other, mainly immunological contexts) frequently show (similar to virus infections) : (a) interactions with components of the PI3K and Akt signaling pathway as well as inhibition or promotion of phosphoinositide synthesis, (b) reduced p53 gene expression, inhibition of the activity of p53 protein, or induction of p53 degradation, and (c) activation of HIF-1 (mainly by stabilization of HIF-1alpha) (XREF_FIG)."
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"37 In previous study, KIF23 has been identified as a novel transcriptional target gene of p53,38 which is similar to our results; knockdown of KIF23 significantly decreased the expression of p53, p21 and BAX, indicating that knockdown of KIF23 may inhibit the p53 signalling pathway."
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"The experimental results show that the simulated structural phosphorylation P53 constructor (Ad-P53-18D20D) at Thr18 and Ser20 can induce G1 stagnation of normal cell strains after exogenous non-phosphorylation P53 (Ad-P53) administration, indicating that the phosphorylation of P53 at Thr18 and Ser20 is enough to induce P53-mediated glioma cell apoptosis (Nakamizo et al., 2008)."
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"Since acetylation of p53 is often required to activate p53, and since Hdac1 and Hdac2 were previously shown to regulate p53 acetylation, the acetylation state of p53 in the DP during mid-anagen (P28) was tested by immunostaining with a series of antibodies that specifically recognize different acetylated lysine residues of activated p53 (Supplementary Fig. 5a, b)."
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"Interestingly, an atypical E3 ligase E4F1 ubiquitinates p53 to promote p53-dependent transcriptional program specifically involved in cell cycle arrest, but not apoptosis; similarly, this ubiquitination pattern does not affect its degradation or cellular localization (Le Cam et al., 2006)."
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"However, it increased the expression of P53 protein significantly only in HL60 cells when compared to their untreated control.These results demonstrated that compound 1c caused apoptosis in HL60 and leukaemia SR cells by suppressing the antiapoptotic Bcl2 protein, activating the apoptotic Bax protein in both types of cells, and activating the P53 protein in HL60 cells."
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"Since p53 phosphorylation at Ser15 has been shown to increase p53 stability and enhance its transcriptional activity XREF_BIBR, XREF_BIBR, our observations suggest that the higher p21 protein level in the Bat3-KD cells is unlikely to be due to increased p53 transcriptional activity."
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"Second, while previous studies have produced a correlation between Sirt1 and p53 in promoting the differentiation of hESCs [XREF_BIBR], our studies provide the first physiological evidence to prove that the acetylation of p53 at K120 and K164, which is inhibited by Sirt1, is required to activate p53 response to induce hESC differentiation."
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"Consistent with loss of p53 specifically driving the effect of the CRISPR p53 knockout on BTZ sensitivity, we observed that H1975-p53KO-GFP cells were significantly less sensitive to 5 nmol/L BTZ than H1975-Control cells (20% vs. 10% viable after 48 hours; P < 0.01; Fig. 1D), whereas p53 expression restored sensitivity to BTZ (12% viability at 48 hours; P < 0.05 for comparison with p53KO-GFP; Fig. 1D)."
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"Phosphorylation of p53 in response to stress disrupts its binding with HDM2, blocks ubiquitination and proteolysis, and results in a rapid increase in p53 protein levels, allowing p53 to enter the nucleus, bind to DNA, and induce expression of genes controlling cell cycle, apoptosis, DNA repair, and cellular senescence [XREF_BIBR]."
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"Genetic alterations located in the retinoblastoma (RB1) (chromosome 13q14.2) and TP53 (chromosome 17p13.1) genes cause inactivation of the RB1 and p53 proteins, and are significant genomic modifications involved in osteosarcomagenesis, which may also contribute to metastatic disease."
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"The regulation of p53 stability and activity involves many proteins, such as the antagonist MDM2 that binds the transactivation domain and also targets p53 for ubiquitination and degradation, or the kinases DNA-PK and ATM that phosphorylate p53 at several of its many sites for post-translational modification [XREF_BIBR, XREF_BIBR]."
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"Inhibition, silencing, or deletion of PAI-1 significantly attenuated H O -induced p53 expression and senescence in both human and mouse astrocytes [44], suggesting that an increase in PAI-1 mediates H O -induced astrocyte senescence probably through inducing p53, although the mechanism underlying PAI-1 induction of p53 remained unclear at the moment.Tumor suppressor p53 is a master controller of the cell cycle and inducer of cell senescence."
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"We found that although the total p53 protein level was not changed significantly, the nuclear p53 protein level was progressively reduced, and correspondingly, the cytoplasmic level of p53 progressively increased, suggesting an increase in p53 nuclear to cytoplasmic translocation after 4-12 h of LPS stimulation (XREF_FIG)."
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"Moreover, immunoblotting analysis of the p53 signaling pathway proved that Bcr/Abl‐R6 efficiently increased p53 protein levels and activated p53 pathway proteins such as p53 up‐regulated modulator of apoptosis (PUMA) and phorbol‐12‐myristate‐13‐acetate‐induced protein 1 (NOXA) (Figure 4B) in a dose‐dependent manner."
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"Additionally, the disruption of the interaction between p53 and Hdm2 inhibited the Dex-mediated ubiquitination of GRα and p53 within human umbilical endothelial cells, suggesting that the Dex-mediated downregulation of GRα requires the association of GRα with p53, the association of p53 with Hdm2 and the ligase activity of Hdm2."
| PMC
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"Given that enhanced p53 phosphorylation at S392 is associated with mitochondrial translocation and proapoptotic activity of p53 (44) and was shown to increase p53 tetramerization, stability, and the tumor-suppressing activity of p53 (45), we tested whether p53 S392 is increased in cells lacking Kv1.3."
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"Indeed, phosphorylation of p53 activates the release of cytochrome c and caspase-9 via target genes such as Bax (BCL-2 [B-cell lymphoma-2] associated protein), Bak (BCL-2 homologous antagonist and killer), Noxa (damage), and PUMA (p53 upregulated modulator of apoptosis) [XREF_BIBR]."
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"Effects of PS-MPs and RJ on protein expression of p53, Bcl-2, Bax, Caspase-3, and Hsp70-2
The IHC staining of p53, Caspase-3, Bax, and Hsp70-2 protein expression significantly increased (P<0.05) in p53 (Figure 7), Bax (Figure 9), Caspase-3 (Figure 10), and Hsp70-2 (Figure 11) germ cells in the cross-sections of the PS-MPs received group compared to the control and RJ group."
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"P53 plays a pivotal role for senescence induction; the DNA damage response activates ataxia telangiectasia (ATM) and Rad3-related (ATR) kinases, which in turn activate the p53/p21 axis by phosphorylation of both p53 and its ubiquitin ligase Mdm2, leading to the stabilization of p53 levels [51]."
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"Activation of AKT-1 and its other isoforms have been implicated in cell survival pathways in human cancer cells through its phosphorylation of the ubiquitin ligase MDM2, which in turn promotes the MDM2 mediated ubiquitination and degradation of p53, which disrupts the p53 intrinsic apoptotic program."
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"embryos.13,15,16 Indeed, Mdm2-nullizygosity induces stabilized, fully active wild-type p53, while combined expression of wild-type p53 and p5325,26,53,54 in p5325,26,53,54/C embryos merely causes modest p53 activation, as only wild-type p53 subunits are active while p5325,26,53,54 subunits are transactivation-dead."
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"This necessitates the inclusion of regulators of p53 mRNA translation that are induced by DNA damage, such as HuR and miR-125b, in the regulatory model of p53 expression in response to genotoxic stress.Therefore, to understand the translation regulatory network that controls pulsatile p53 expression in response to DNA damage, we have adopted an approach combining computational modeling and experimental validation in a reiterative manner."
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"Although Bortezomib increased the levels of p53 and increased the expression of pro apoptotic target genes in ERalpha+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERalpha+ breast cancer cells through suppression of ERalpha expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53."
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"In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 (-/-) mice, while, similarly, p53 expression in p53 (-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons."
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"Interestingly, while MDH1 does not interfere with the p53 and MDM2 interaction, overexpression and depletion experiments show that MDH1 inhibits p53 ubiquitylation and prevents MDM2 dependent cytoplasmic retention of p53, thereby promoting apoptosis in response to glucose starvation 61."
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"For example, MDM2 can directly bind to p53 to inhibit its transcriptional activity; quickly enhance the ubiquitination and degradation of p53 through ubiquitin-E3 ligase; and promote p53 degradation by blocking p53 's transport from the nucleus to the cytoplasm XREF_BIBR XREF_BIBR."
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"Studies have shown that PAI-1 plays a crucial role in both stress-induced and replicative aging in cells and can be readily detected in accelerated and physiological aging models.34 Although the precise process remains unknown, numerous research studies have showed that PAI-1 production can be triggered by different inflammatory agents, such as IL-6 and TNF-α.35 The TP53 gene produces the P53 protein, essential for regulating cell growth and apoptosis."
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"Human DYRK2 is a critical component in the Hedgehog signaling pathway XREF_BIBR; acts as an molecular assembler of an E3 ubiquitin ligase complex, which plays a crucial role in regulating normal mitotic progression XREF_BIBR; and functions in the DNA damage signaling pathway by phosphorylating p53 thereby initiating a p53 apoptotic response XREF_BIBR."
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"Activated p53 (protein product of TP53) is a DNA-binding transcription factor that targets different proteins that are either involved in apoptosis (e.g., Bad, Bax, Puma, Fas, Apaf1, Noxa) or can induce cell cycle arrest (e.g., BTG2, CDNK1/p21/pRb/E2F1 pathway, GADD45) and activate DNA repair mechanisms (e.g., p48, XPC, PCNA, DDB2) after exposure to UV light, ionizing radiation or other DNA-damaging agents [17]."
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"Over-expression of hepatic p53 and p63 was achieved by tail vein injection of adenoviral vectors activating p53 (SignaGen Laboratories, USA, ref # SL100,777), p63 (SignaGen Laboratories, USA, ref # 189SL100,865) and GFP (SignaGen Laboratories, USA, ref # SL100,833) (1 x 10 9 VGml -1)."
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"Overall, the complex relations between AKT and ROS in C2C12 myoblasts could be exquisitely regulated by different cellular stimuli, which can be seen in our present study that displayed opposite correlation between AKT and ROS by merely treating C2C12 cells with different magnitudes of stretch.Second, we uncovered that p53 Ser389 phosphorylation promoted p53 to translocate into mitochondria, and ROS-dephosphorylated AKT was necessary but not sufficient to phosphorylate p53 Ser389."
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"Increased p53 expression in TAMs induces senescence and activation of the p53‐dependent SASP, while an APR‐53‐induced increase in p246 expression leads to suppression of M2‐polarized myeloid cells and increased T‐cell proliferation to enhance the efficacy of the immune checkpoint blockade [140]."
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"Chronic hyperglycemia followed by an increase in cytoplasmic glucose concentration causes C-terminal glycosylation of the tumor suppressor p53, which then activates the transcriptional activator p53, resulting in its translocation to the nucleus and the initiation of transcription of several p53-dependent genes xref , xref ."
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"HBeAg and its precursors could disrupt p53-NUMB and HDM2-NUMB interactions and tricomplex p53-HDM2-NUMB formation, inhibit the acetylation and translocation of p53 from cytosol to the nucleus, promote HDM2 mediated ubiquitination and degradation of p53, and suppress p53 dependent apoptosis."
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"To evaluate whether the p53 pathway was activated in these PIM1 containing prostate cancer cells, we carried out quantitative reverse transcriptase-PCR (qRT-PCR) analysis of mRNA from cells expressing PIM1 at early and late passages (XREF_FIG), and examined the levels of three p53 activated genes, p53 inducible nuclear protein 1, DNA-damage inducible transcript 4, and p21."
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"Notably , over 70 % of osteosarcoma has structural variants or mutations in the TP53 gene , Ewing sarcoma is rarely mutated for TP53 due to EWS-FLI1 's inhibitory effect on TP53 , non-uterine LMS has a high rate ( ~ 50 % ) of TP53 mutation , and well - and de-differentiated LPSs are defined by amplification of MDM2 ."
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"Indeed, the inactivation of p53 generally caused by TP53 gene mutations followed by loss of functionality through a variety of non-mutational regulatory failures, such as alterations in intracellular protein location, is a common phenomenon reported in >50% of various human cancers (60,61)."
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"Taken together, these results demonstrate that down-regulation of p53 expression or inhibition of p53-dependent gene transcription enhanced chemoresistance to CDDP in MCF-7 and MCF-7 cells under both treatments, suggesting a key role of p53 in overcoming the chemoresistance of MCF-7 cells."
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"This finding indicates that Nur77 may affect the global gene expression via p300, and it would be of interest to find out whether Nur77 can modulate the HAT activity of other molecules.2.2.3 p53 The direct interaction of Nur77 with the tumor suppressor p53 is shown to block p300 induced acetylation of p53, which subsequently results in a decrease in Mdm2 transcript levels, and thus prevents p53 from Mdm2 mediated proteasomal degradation [56]."
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"Here we report the first account of the dynamics of mutation induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation."
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"The intimate addiction of cancer cells to the sustained activity of E6 represents an advantage for the development of anti-cancer drugs, since perturbing E6 activities can restore the intracellular levels of active p53 and reactivate p53 mediated pathways, leading to oncogene induced senescence and eventually apoptosis of cancer cells 20."
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"One particularly important mechanism is the phosphorylation of p53, which prevents p53 degradation and allows p53 to function as a transcription factor to hundreds of genes, resulting in the production of several cell-cycle inhibitors such as p21, which inhibits the cyclin D–CDK4/6 complex, which is critical to the G1/S checkpoint [8,9]."
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"These results indicate that gemcitabine would only be effective in p53 wild-type tumors, which underlines the clinical relevance of this study, since ATRTs rarely carry TP53 mutations.12 Furthermore, we show that the p53 inhibitor SIRT1 is overexpressed in ATRT compared to other CNS tumors, which might explain why p53 is often suppressed in ATRT, contributing to its highly malignant behavior.In correlation with p53, we found that NF-κB is activated upon gemcitabine treatment in our ATRT models, and we suggest that this activation works synergistically with p53 to induce apoptosis."
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"We assume that the deactivation rate of the single gene copy is constant, and that the deactivation events are independent, so that : As far as the activation rates are concerned, we recall that the p53 protein is a transcription factor for both Mdm2 and PTEN XREF_BIBR, and that p53 phosphorylation enhances p53 activity in transcription XREF_BIBR."
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"Analysis of p53 chromatin immunoprecipitation sequencing (ChIP-seq) experiments performed in HCT116 cells XREF_BIBR indicates the presence of a significant peak of p53 interaction in two independent experiments involving p53 activation induced by Nutlin3 or 5 ' fluorouracil (5FU)), at the same position, approximately 800 bp away from the GAS5 transcriptional start site (TSS), indicating that p53 directly controls GAS5 transcription."
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"It is possible that when RNA polymerase is stalled at DNA damage sites, Cdk7 in TFIIH phosphorylates p53 and enhances some p53 mediated function, such as induction of the Cdk inhibitor p21.Recent years have seen the minimalist idea that the cell cycle is driven by a single cycin and Cdk complex become very elaborate."
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"Interestingly, SVCV has been shown to regulate zebrafish p53 function through two distinct mechanisms: SVCV-N protein promotes zebrafish p53 degradation by suppressing K63-linked ubiquitination of p53, whereas SVCV-P protein stabilizes p53 by enhancing K63-linked ubiquitination of p53 (38)."
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"Yang-Hartwich et al. (2015) [40], showed that both in vitro and in vivo OCSC experimental models expressing wtp53 demonstrated a curious mechanism in which p14ARF, a p53-positive regulator, inhibited MDM2-mediated p53 degradation, triggering an imbalance of p53 turnover, wtp53 aggregation, and resistance to carboplatin [40]."
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"44 However, massive expansion of the many copies of TP53 identified in elephants was suggested to increase cellular sensitivity to DNA damage by triggering p53-dependent apoptosis, which leads to efficient removal of mutant cells.14Previous studies have also shown that many genes related to cancer control (including DNA damage and repair, immune response, and tumor suppression) evolved under positive selection, duplication, and amino acid changes in several long-lived lineages, suggesting that they share a mechanism."
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"As indicated in Figure 1 and Table 1, western immunoblotting and/or flow cytometry revealed that the expression of total p53 and phopsho-p53 protein was found to be up-regulated (~2-fold for total and >3-fold for phospho-p53) in the ALDH1B1-overexpressing cells compared to HT29/mock cells."
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"The relationship between p53 and autophagy has been shown to be extremely complex: while the autophagic pathway is regulated by p53 signaling (in general, wtp53 acts as a pro-autophagic factor, but mutp53 displays a suppressive role in autophagy); furthermore, p53 is also a target protein of autophagy [140]."
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"The outcome of p53 activation may depend on the cell type, amount of DNA damage, levels of p53 induced, different p53 post-translational modifications, recruitment of different co-factors to p53, and transcriptional activation of different sets of p53 target genes [XREF_BIBR, XREF_BIBR]."
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"Induction of DNA damage initiates a cascade of signalling with p53 activation (phosphorylation at Ser 15 and Ser 20) and subsequent transcriptional activation of p53 response genes (including p21, GADD45, BAX, PUMA, Bcl2 and NOXA), thus provoking cell cycle arrest and/or apoptosis [ xref ]."
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"Untreated TC28a2 chondrocytes display increasingly elevated deacetylated p53 fluorescence as oxidation level increases using both the mid‐ and N‐terminal p53 antibody (Figures S7 and S8) and is present in an increasingly diffuse, cytoplasmic, and disorganized pattern as H O levels increase (the N‐terminal antibody signal remains mostly nuclear)."
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"The phosphorylation of p53 on Ser15 was demonstrated to prevent p53 negative regulator MDM2 binding and to result in the accumulation and increased transcriptional activation ability of p53.35 These results indicated that aforementioned apoptotic response was induced by a p53 dependent endogenous apoptosis pathway."
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"The network uncovered the central regulatory role of the p53 signaling pathway, and the enrichment of p53 phosphorylation-related genes in both mTEC and mTEC from Dhx9 cKO mice increased the stability of P53 protein through posttranslational modifications (
Figures 7A, B
) (68, 69)."
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"This conclusion is also supported by the fact that in gliomas there was an increase in MDM2, which is a protein responsible for degrading p53, XREF_BIBR - XREF_BIBR while in adenocarcinomas there was an increase in the level of p53, which would be likely to trigger p53 dependent apoptosis in these cells."
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"Cell cycle proteins have been identified to serve important roles in the carcinogenesis of laryngeal cancer, and the upregulation of cellular tumor antigen p53 (p53), p21 and cyclin dependent kinase 1 in the surgical margin of early cancer is associated with local tumor recurrence (10)."
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"Transcriptome sequencing identified the p53 signaling pathway as a key molecular target of SolB, demonstrating its role as a molecular glue in the mouse double minute 2 (MDM2)-p53 interaction, thereby promoting p53 ubiquitination and degradation, which further inhibited p53-related inflammatory and senescence response."
eidos
"iASPP ( 295-828 ) preferentially inhibits p53 over NF-kappaBp65 Based on the fact that iASPP ( 295-828 ) acts as a double-edged sword in regulating apoptosis , by inhibiting either p53 or NF-kappaBp65 , we next investigated whether iASPP ( 295-828 ) preferentially regulates either of these two targets ."
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"Furthermore, our result also demonstrated that knockdown of NR5A2 decreased the expression of p53-related genes (e.g., GADD45A, DDB2, SERPINE1, SHISA5, STEAP3, BAX, RRM2B, CD82) associated with p53 pathway (14), which could be attenuated by TP53 silencing in FaDu cells (
Supplementary Figure 3C
)."
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"The syndrome is caused by pathogenic variants in the TP53 gene (chromosome 17p13.1), encoding the p53 protein, a tumor suppressor that responds to different cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolism changes [83]."
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"This special issue compiles emerging non canonical functions and regulation of p53, including (1) novel mechanisms regulating the expression and activities of p53 and its family members, p63 and p73; (2) p53 proteoforms and binding potential of p53 to local DNA structures; (3) novel oncogenic pathways and stemness regulated by p53; (4) roles of p53 in non canonical cell death; (5) roles of p53 in glucose, lipid, and nucleotide metabolism, and (6) roles of p53 in immunity."
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"However, p53 phosphorylation by specific kinases, e.g., p38, following osmotic cell shrinkage, or ATM (ataxia-telangiectasia-mutated kinase)/ATR (ataxia-telangiectasia and Rad3 related) following cisplatin induced DNA damage stabilizes p53 and hence ensures apoptosis and depresses cell proliferation."
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"As the transactivation ability of p53 is almost entirely dependent on p53 protein levels, ubiquitination of p53 by MDM2 can modulate the activity of p53 as a transcription factor.We previously identified growth arrest and DNA-damage-inducible gene 34 (GADD34; protein phosphatase 1, regulatory subunit 15A/PPP1R15A) as an antigen recognized by serum IgG antibodies in patients with atherosclerosis and acute ischemic stroke (AIS) (12)."
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"Here, using yeast, we show that transient p53 overexpression induced the formation of p53 prion aggregates that were transmitted for> 100 generations, found in lysate pellets, stained with Thioflavin T, and transmitted by cytoplasmic transfer, or transfection with lysates of cells carrying the prion or with p53 amyloid peptide."
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"P53 is well‐recognized to play a key role in cell‐cycle control, DNA repair and cellular stress responses, and recent studies has reported that p53 activation of p53 can regulate apoptosis, cellular senescence and organismal ageing. xref SA‐β‐gal is an extensively utilized marker for cell senescence, and the β‐galactosidase activity can be detected at pH 6.0 in replicative or induced senescence cells but undetectable from proliferating cells. xref Levels of p53 often gradually increase during the process of replicative senescence, whereas the presence of SA‐β‐gal marker can distinguish senescent cells during cell passages independent of DNA synthesis. xref Thus, a time‐lag may exist between the time‐point of increased p53 levels and the presence of SA‐β‐gal activity."
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"It is unclear how H1.2 translocation to the cytoplasm is stimulated, but phosphorylation of its T146 residue (H1.2T146-P) together with p300-mediated acetylation of p53 has been shown to block p53-H1.2 binding, allowing p53 to activate transcription of its target genes such as BAX and thereby promote cell death (Kim et al. 2012)."
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"The investigators hypothesize that, by inhibiting MDM2 expression, the MDM2 oncoprotein level will be reduced and the MDM2 negative feedback inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53 mediated therapeutic effects."
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"STZ treatment inhibits phosphorylation of p53 on Thr 155, which is induced by COP9 signalosome (CSN) and is required for p53 degradation, and results in increased GlcNAcylation on Ser 149, thus, blocking p53 from being phosphorylated and degraded by ubiquitin-proteasomal mechanism."
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"Although functional relevance of each specific lysine acetylation in p53 C-terminal domain in disabling p53 from interacting with VprBP remains to be determined, it seems clear that p53 acetylation allows for very tight regulation of VprBP-induced disturbance of p53 protein stability and transcriptional activity."
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"Our results showed that TRIM72 enhances the overall ubiquitination activity of RLE cells that is linked to bleo induced p53 upregulation as well as Ser 15 phosphorylation of p53, suggesting that these post-translational modifications are the target mechanisms of TRIM72 modulation of p53, collectively leading to suppressed transcription of p53 target genes."
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"In contrast to TP53 missense mutations that lead to p53 nuclear accumulation, and, thus, intense p53 staining by IHC (Figure 1), nonsense, frameshift, and indel alterations were not easily detected by IHC due to the low basal p53 expression in normal prostate and p53-wild-type PC [48]."
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"These data suggest that p68, p53 and Delta133p53alpha may form part of a complex feedback mechanism to regulate the expression of Delta133p53, with consequent modification of p53 mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild type p53."
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"We, therefore, demonstrate the key role of the MDM2-p53 interaction in neuronal survival after ischemia and identify the SNP309 in the MDM2 gene promoter as an independent factor for predicting functional prognosis of patients with stroke.The p53 protein is effectively antagonized by its direct interaction with MDM2, which represses transcription of p53 target genes and promotes p53 degradation via ubiquitination, all leading to p53 inactivation."
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"Overexpression of apoptosis stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor and epidermal growth factor receptor and SOS1 pathway impairs the pro apoptotic role of ASPP2."
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"Furthermore, targeting p53 null cells requires a different approach altogether, which can be based on the identification of synthetic lethality (increased sensitivity to inhibition of another pathway in the absence of p53) or induction of a p53 like response by the activation of the p53 family member s p73 or p63 [XREF_BIBR]."
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"XREF_BIBR Thus, since the E3 ligase activity of MDM2 is not affected by Nutlin, the remaining low levels of complex formation between MDM2 and p53, although insufficient for mediating p53 polyubiquitination and destabilization, is sufficient for mediating p53 monoubiquitination which is known to promote p53 trafficking to mitochondria."
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"It has been shown by DNA binding, transcriptional activation and tumor suppressing assays that the incorporation of a second mutation into oncogenic p53, referred to as second-site suppressor mutation, can rescue the normal activity of p53 as described later in the text for the current hot spot mutations."
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"Our further studies on the role of TRIM26 in regulation of p53 reveal that this Ring E3 ligase can ubiquitinate p53 and lead to its proteolytic degradation, consequently inactivating p53 and promoting the growth and proliferation of colorectal cancer cells in culture and in xenograft."
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"In addition to the typical full-length p53, TP53 produces at least 12 truncated subtypes through the alternative initiation of translation, the use of alternative promoters, and alternative splicing, which can positively or negatively regulate the activity and function of full-length p53 [281, 310]."
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"GADD45 stabilizes phosphorylation of serine 15 of p53 providing a positive feedback signal in activation of the p53 pathway, Plk3 phosphorylates p53 on serine 20 and enhances p53 stabilization, and p53 dependent activation of Plk2 prevents mitotic catastrophe after spindle damage."
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"We show that the C-terminal sequence of PEPD binds to the PRD in p53, which allows PEPD to accomplish two important tasks : (1) to prevent nuclear p53 phosphorylation in its transactivation domain andto reduce free nuclear p53 level, leading to inhibition of p53 trans-activation and trans-suppression activities, and (2) to prevent mitochondrial translocation of nuclear and cytosolic p53 by preventing p53 from binding to MDM2 (Figs."
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"Genetic mutations in the p53 gene or downregulation of p53 caused by an increase in the expression level of the p53 ubiquitin ligase MDM2 proto-oncogene (MDM2) were identified as mechanisms that suppress senescence, and these processes were observed to cause therapeutic resistance (8)."
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"The direct mitochondrial apoptogenic role for p53(A347D) is supported by our finding that PFT-μ, which has been shown to attenuate p53 association with mitochondria and preclude p53 binding to Bcl-2 and Bcl-xL, both decreases the amount of p53 found in the mitochondrial fraction and rescues p53 cells from etoposide-mediated cell death (52,73)."
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"These results from genetically engineered mouse models, together with other results from cell cultures, have demonstrated that while MDM2 can effectively degrade mutp53 in cultured normal and cancer cells as well as normal mouse tissues, tumors develop specific mechanisms to impair MDM2-mediated mutp53 degradation, leading to mutp53 accumulation in tumors (7, 24–26, 59)."
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"A number of TP53 missense mutations produce full-length p53 proteins that frequently have a prolonged half-life with accumulation of inactive protein, whereas frameshift mutations do not usually lead to accumulation of p53, and nonsense mutations generally result in an unstable protein."
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"A detailed description of the model development, model simulation, and parameter estimation is provided in the Supplemental Information.The mathematical model was fitted to the experimental datasets that captured the temporal profiles of cisplatin-DNA binding dynamics; total levels of Chk1, Chk2, p53, and p21; the activation of Chk1, Chk2, and p53; as well as cell viability responses in breast and lung cells."
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"However, HeLa cells, in which human papillomavirus E6 protein inhibits the phosphorylation of p53 and induces p53 degradation (51), failed to activate a G checkpoint (Supplementary Fig. S2B), further supporting the main role of p53 signaling in ATRi-induced G checkpoint activation.Taken together, these results show that ATR inhibition leads to the accumulation of DSB damage and an ATM-p53–mediated G checkpoint response, protecting cells from entering replication."
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"Simple readouts for p53 activation under nucleolar stress conditions are an increased p53 protein levels (stabilization or accumulation following blockage of ubiquitin-proteasomal degradation), reduced p53 binding to MDM2/HDM2, increased p53 mRNA levels under a long-lasting stress, elevated mRNA levels of p53 target genes, typically CDKN1A (p21) and BAX, and corresponding cell phenotypes such as cell cycle arrest, autophagy, DNA repair, senescence, or apoptosis 89."
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"In response to ER stress, erastin activates the PERK-eIF2α-ATF4-CHOP pathway, and the activation of C/EBP homologous protein (CHOP) results in the increased expression of p53 upregulated modulator of apoptosis (p53-independent PUMA), which participates in synergistic effects in ferroptosis and apoptosis."