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"To investigate whether epithelial cells acquire the ability to suppress p53 induction in adjacent stromal cells in the course of neoplastic transformation, we took advantage of normal primary human bronchial epithelial cells immortalized with human telomerase (NHBET) and their in vitro transformed derivatives stably expressing mutant H-Ras and short-hairpin RNA specific for p53, which strongly downregulates their p53 protein levels (XREF_FIG)."
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"Consequently, when we blocked the expression of miR-1228, p53 was released and enforced the inhibition of miR-1228, thereby promoting the accumulation of p53; however, miR-1228 is upregulated in HCC tissue in which p53 is downregulated, repressing p53 expression to relieve its inhibition on miR-1228 expression in turn, which creates a feedback regulation to ensure persistent low protein levels of p53 to control the malignant phenotype."
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"In addition, knockdown of p53 expression by p53 siRNA significantly inhibited the protein level of Fas and CD95, PUMA, cleaved caspase-8 and cleaved caspase-3 (XREF_FIG), cell growth-inhibitory effects (XREF_FIG), and apoptosis (XREF_FIG) after treatment with ESE in HCT 116 cells."
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"Two p53 specific small interfering RNA (siRNA) oligos (si-p53-1 and si-p53-2) targeting different mRNA regions of p53 were used to effectively repress p53 expression in HCT116 (p53 +/+) cells, which resulted in a corresponding 50-60% reduction in ERAP1 mRNA (XREF_FIG) and protein (XREF_FIG) levels."
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"The tumor-suppressive role of miR-34a was confirmed by Luan et al. who also found that miR-34a levels reflect the status of tumor suppressor p53, and that miR-34a could activate the p53 signaling cascade of p53 expression independently, possibly through targeting of SIRT1 [XREF_BIBR]."
"To investigate possible pathways linking Gas2 to p53, a yeast two-hybrid screen swas performed, indicating m-calpain as a strong Gas2- interacting protein. Moreover, we demonstrate that Gas2 physically interacts with m-calpain in vivo and that recombinant Gas2 inhibits calpain-dependent processing of p53."
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"While in WT cells, TFEB overexpression elevates both the mRNA and protein of p21 without significantly altering p53 protein levels (Supplementary Figure S2A–C), the TFEB-mediated induction of p21 was almost completely inhibited in the p53 null cell line (SAOS-2 p53-null) (Figure 2A,B and Supplementary Figure S2D)."
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"Immunohistochemistry results showed that p53 and caspase-3 were expressed at lower levels in all neural cell types in the WT control group, while astrocytic YY1 deletion significantly increased fluorescence intensity levels of p53 (Fig. 7A) and caspase-3 (Fig. 7B) in astrocytes (GFAP cells) as well as non-astrocytes (GFAP cells) in all regions examined."
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"These results demonstrate an association between EBNA1 expression and the expression of p53-inhibiting genes in the MKN-45 cell line, suggesting p53 suppression following upregulation of negative regulators.According to our findings, the mRNA level of p53 was downregulated in the cells transfected with EBNA1."
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"For instance, RBM10 expression can reduce p53 expression, inhibit apoptosis, and promote cell growth as well as other transformation-associated processes as shown in human lung cancer cell lines A549, p53-deficient H1299 (Sun et al., 2019), and RBM5-null GLC20 (Loiselle et al., 2017)."
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"Interestingly, silencing of BAFFR yielded a strong reduction in total p53 levels (Figure 7—figure supplement 1C), while silencing of BCMA or TACI did not reduce p53 levels, and instead increased total p53 levels, similarly to what we observed for TACI and BCMA in THP-1 cells when measuring SASP factor levels (Figure 5C)."
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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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"Several studies have reported that tumors, including lung cancer, are strongly associated with inflammation, and upregulation of the ribosome biogenesis rate might be involved in tumor transformation in tissues affected by chronic inflammation, upregulation of rRNA transcription results in increased MDM2-mediated degradation of P53 proteasome, which reduces P53 expression and promotes tumorigenesis (Donati et al., 2011)."
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"A549/DDP cells were pretreated with 30 μM PFT‐α (a concentration that did not cause significant cytotoxicity in cells) for 30 min prior to addition of As S Inhibition of p53 by PFT‐α partially restored the protein levels of p53 and PD‐L1, which were changed by As S treatment (Figure 6a–c)."
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"In the study of renal fibrosis, SERPINE1 also appears to up-regulate renal p53, since p53 protein levels are increased by sustained renal SERPINE1 expression and p53 stable suppression in SERPINE1 transductants, attenuating the induction of fibrotic factors, reversing the proliferative defects, and reducing the susceptibility to cell death."
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"Three novel single nucleotide variants were shown to disrupt miR-125b binding to their TP53 target causing upregulation of p53 expression and an increase in apoptosis, while in contrast the rs78378222 CC SNP located in the polyadenylation signal (PAS) and not a putative miRNA binding site, was shown to reduce p53 expression and subsequently reduced apoptosis."
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"Published reports have implicated catalytic function because the modulation of USP18 increased the ISGylation of a wide range of proteins, including ISGs and tumor suppressors that can regulate tumor growth.39 42 43 44 45 For example, increased ISGylation of ISGs and the tumor suppressor p53 is hypothesized to increase tumor intrinsic IFN signaling or p53-dependent transcription, respectively, resulting in decreased tumor growth.42 Nevertheless, a causal relationship between deISGylase activity and cancer survival has not been established."
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"In addition, both groups observed a significant difference regarding P53 gene expression.Thus, a decrease in RNF38 gene expression results in increasing P53 and reducing sperm motility.Regarding the comparative assessment of P53 and RNF38 genes expression in patients and that of the normal subgroup of C, an increase and decrease were observed in the expression level of P53 and RNF38 genes in the males with asthenozoospermia compared to that of normal individuals, respectively."
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"Accordingly, circ‐36683 overexpression resulted in increased expression of p53, p21, and p27, but decreased expression of cyclin E1 and CDK2, while circ‐36683 knockdown downregulated the expression of p53, p21, and p27, and upregulated the expression of cyclin E1 and CDK2 (Figure 6j and Figure S2)."
"# Ariadne: Our results indicate that NQO1 regulates degradation of p53 in the proteasomes by a mechanism that is independent of both Mdm-2 and ubiquitin. [Regulation] # Ariadne: Inhibition of NQO1 Activity Induces Mdm-2-Independent p53 Degradation That Is Blocked by p14 ARF . [Regulation]"
"PCNA and DDB1/CUL4A complexes were found to physically interact with p53 tumor suppressor and its regulator MDM2/HDM2. The isolated CUL4A complexes display potent and robust polyubiquitination activity towards p53 and this activity is dependent on L2DTL, PCNA, DDB1, ROC1 and MDM2/HDM2."
"Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. Further experiments revealed that overexpression of beta-arrestin 2 enhanced the p53-mediated apoptosis while suppression of endogenous beta-arrestin 2 expression by RNA interference technology considerably attenuated the p53-mediated apoptosis"
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"In fact, even though it has been reported that IL-6 activates STAT3 18 and that activated STAT3 binds to the TP53 gene promoter repressing the transcription of TP53 mRNA, 19 we found that no significant change occurred in the transcription level of TP53 mRNA in the NCM460, HepG2, SW1990 and LS174T cell lines (XREF_FIG)."
"Akt (PKB) directly phosphorylates multiple protein targets of relevance to apoptosis (Figure 2B), suppressing cell death clearly within the intrinsic pathway (e.g., BAD inactivation, human caspase-9 suppression) and possibly also the extrinsic pathway (e.g., FasL expression) in some types of cells."
"In addition, treatment of cells with the PKC activator phorbol ester stimulated the ubiquitination of p53 and reduced its ability to accumulate after stress. H7 did not induce the phosphorylation of human p53 on Ser-15 (Ser-18 in mouse protein), a modification that occurs in response to DNA damage and leads to the release of MDM2 and to transactivation by p53"
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"Furthermore, to investigate whether cell death is triggered via p53-dependent or -independent mechanisms, we assessed the protein level of PUMA, which is a p53-upregulated modulator of apoptosis (Figure 6C), and the phosphorylation level of p53 tumor suppressor in AGS and HT-29 cells (Figure 7A)."
"It has been proposed that ARF is expressed only when an E2F signaling threshold is exceeded following oncogenic activation. The main activity of ARF is its ability to bind to p53 inhibitors and to control ribosome biogenesis. Human double minute (HDM2) [mouse double minute 2 (Mdm2) in mouse] and ARF protein binding 1 (BP1)/Mule are two specific E3 ubiquitin ligases that mediate p53 degradation through ubiquitination."
"We now show that p53 and its inhibitor MDM2 (HDM2 in human cells) are together in the nuclei of H7-treated cells and can be co-immunoprecipitated. Despite this association of p53 with the ubiquitin ligase MDM2, ubiquitinated p53 was not detected in H7-treated cells. Furthermore, co-treatment with H7 and the proteosome inhibitor LLnL prevented the accumulation of ubiquitinated p53 that was observed in cells treated solely with LLnL."
"We investigated the role of the ubiquitin-conjugating enzyme UBCH7 in nuclear receptor transactivation. Using transient transfection assays, we demonstrated that UBCH7 modulates the transcriptional activity of progesterone receptor (PR) and glucocorticoid, androgen, and retinoic acid receptors in a hormone-dependent manner and that the ubiquitin conjugation activity of UBCH7 is required for its ability to potentiate transactivation by steroid hormone receptors (SHR). However, UBCH7 showed no significant effect on the transactivation functions of p53 and VP-16 activation domain. Depletion of endogenous UBCH7 protein by small interfering RNAs suggests that UBCH7 is required for the proper function of SHR. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of UBCH7 onto estrogen receptor- and PR-responsive promoters. Additionally, we show that UBCH7 and E6-associated protein (E6-AP) synergistically enhance PR transactivation. We also demonstrate that UBCH7 interacts with steroid receptor coactivator 1 (SRC-1) and that UBCH7 coactivation function is dependent on SRC-1. Taken together, our results reveal the possible role of UBCH7 in steroid receptor transactivation and provide insights into the mechanism of action of UBCH7 in receptor function."
"The life history of cancer cells encompasses a series of genetic missteps in which normal cells are progressively transformed into tumor cells that invade surrounding tissues and become malignant. Most prominent among the regulators disrupted in cancer cells are two tumor suppressors, the retinoblastoma protein (RB) and the p53 transcription factor. Here, we discuss interconnecting signaling pathways controlled by RB and p53, attempting to explain their potentially universal involvement in the etiology of cancer. Pinpointing the various ways by which the functions of RB and p53 are subverted in individual tumors should provide a rational basis for developing more refined tumor-specific therapies."
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"Based on these observations, we hypothesized that ATRA upregulates p53 to inhibit HBV replication in human hepatoma cells.To confirm that ATRA inhibits HBV replication by upregulating p53 levels, we knocked down p53 in HepG2-NTCP cells and expressed ectopic p53 in Hep3B-NTCP cells before HBV infection and ATRA treatment."
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"There was a significant reduction (ranging from 22% -30%) in endogenous levels of the cleaved caspase-3 protein when either the MEK and ERK pathway or the mitochondrial arm of the p53 pathway was suppressed, indicating that while the p53 protein likely influences apoptosis, as induced by B. burgdorferi in mature MO3.13 human oligodendrocytes, the MEK and ERK pathway affects inflammation, p53 levels, and apoptosis."
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"The hematologic phenotype of Elp3 mice was thus caused by a p53-dependent checkpoint.To further assess the effect of the loss of p53 on the functionality of Elp3-deficient HSPCs, we compared BM recovery in Elp3 and Elp3/Trp53 mice after initial myeloablation through treatment with 5-fluorouracil (5-FU; Fig. 8, E–G)."
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"Given the opposing responses of MDM2 and p53 elicited by HB-EGF (Fig. 3A), the enhanced association of p53 and MDM2 by HB-EGF stimulation (Fig. 3B) supported the hypothesis that MDM2 may negatively regulate p53 expression, possibly by stimulating direct binding of MDM2 to p53 following HB-EGF treatment [33]–[35]."
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"Knockdown of DNAJA1 in HNSCC cell lines carrying unfolded mutp53 significantly decreased the levels of mutp53, filopodia/lamellipodia formation, migratory potential, and active forms of CDC42/RAC1, which were not observed in HNSCC cells with DNA contact mutp53, wild-type p53, or p53 null."
"p14ARF tumour suppressor stabilises and activates p53 by directly interacting with (H)Mdm2 [(human) murine double minute 2 homologue] and inhibiting its E3 ubiquitin ligase activity. Expression of p14ARF protects p53 from (H)Mdm2-mediated ubiquitylation but has no effect on the auto-ubiquitylation activity of (H)Mdm2 [18]."
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"During the stimulation of the intrinsic apoptosis ways that leads to start the caspase-dependent downregulation of cancer proliferation and ultimately results in cell death, increased p53 expression reduced the number of cells37
38.The outcomes of this investigation prompted the overexpression of p53 in the TMZ treated group that supports to initiation of apoptosis in mammary cancer cells."
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"As shown in Supplementary Fig. S7, miR-3622 KO increased the expression of p53-induced genes (pro-apoptotic genes: BAX, BBC3, PMAIP1, TP53I3, GADD45A, and GADD45B; growth arrest genes: CDKN1A, ZMAT3, SESN1, and RM2B), but decreased the expression of p53-repressed genes (cell cycle genes: CCND1, CCND2, CCNB1, and CCNB2)."
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"Since it has been shown that aspirin, at very high concentration (5 mM) reduced the phosphorylation of STAT3 [XREF_BIBR] and that activated STAT3 binds to the TP53 gene promoter repressing the transcription of TP53 mRNA [XREF_BIBR], we first evaluated the transcription level of TP53 mRNA in the NCM460 and HepG2 cells by Real-time RT-PCR analysis after exposure to progressive concentrations of aspirin."
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"Finally, instead of down-regulation of FOXM1 expression as observed in Detroit 562 and Ca9-22 cells (XREF_FIG), decreasing the p53 level by p53 shRNA in STAR cells, which contain endogenous wild-type p53, increased the levels of FOXM1 (XREF_FIG), suggesting that wild-type p53 inhibits FOXM1 expression."
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"Furthermore, blocking expression of wtp53 in OCI-AML3 cells by treating them with a small interference RNA against p53 (sip53), which effectively decreased p53 expression (XREF_SUPPLEMENTARY), prevented DCA induced decreased daunorubicin clearing, whereas a control siRNA did not show any effect (data not shown)."
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"The CSP (DGIWKASFTTFTVTKYWFYR) and CSP7 (FTTFTVT) peptide derivatives of caveolin-1 were shown to elicit anti-fibrotic effects through inducing microRNA-34a expression of p53, which subsequently inhibited the expression of sirtuin 1 (SIRT1), increased p53 expression, and led to blockade of platelet-derived growth factor receptor (PDGFR)-β activation and prevention of pulmonary fibrosis in bleomycin-injury mouse models [44]."
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"23 If accumulated in its active form, P53 promotes apoptosis to remove mutant progenitor B cells and tumorigenesis.24 25 26 However, impaired P53 expression and/or activity leads to genomic instability and B cell transformation.27 28 29 Here, we show that TIA1 and TIAL1 not only limit the expression of P53 in pro-B cells but they also modulate a global RNA splicing program required for the expression of genes involved in DNA damage sensing and repair in pro-B cells."
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"In our previous studies [XREF_BIBR], we demonstrated that (a) the basal level of endogenous p53 protein is much higher in mouse Ube4b null MEFs than in parental wild-type MEFs; indicating Ube4b plays a critical role in regulating basal level of p53 in unstressed conditions; (b) overexpression of mouse Ube4b decreased the level of p53 in Mdm2 null MEFs, suggesting that the Ube4b dependent Mdm2 mediated p53 degradation is not absolute."
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"In addition, high expression of ITGB1 and low expression of p53 has been found to act as adverse prognostic factors in NSCLC.35 P53 induced miR-30e-5p inhibits cell metastasis in colorectal cancer by targeting ITGB1.36 All these findings support our conclusion that miR-374b inhibits the progression of NSCLC by downregulating ITGB1 and promoting p53 expression."
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"As shown in Figure 6, in H1299 cells, while the WT p53 repressed PDCD4 promoter activity, the truncations of the p53 C-terminal domain (Δ372–393 and Δ370–393) resulted in the loss of p53-mediated PDCD4 promoter repression, which suggests that the sequence between aa374 and aa370 of p53 (which contains methylation and acetylation sites) is critical for p53-mediated PDCD4 repression."
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"However, Jung et al. (167) have identified each mTOR kinase as being able to bind to p53 and induce a senescence phenotype, albeit the studies were performed in a PTEN-deficient MCF-7 cells and mouse embryo fibroblasts with dysregulated PI3K/AKT signaling.Increased expression of YPEL3, a p53-regulated protein known to induce senescence (145) also has been proposed to induce senescence in antiestrogen treated MCF-7 cells (110)."
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"Mechanistically, BRD7 decreased phosphorylation and activation of MDM2 via inactivating its upstream kinase AKT depending on the bromodomain of BRD7, therefore BRD7 significantly reduced the amounts of phosphorylated MDM2 binding with p53 eventually decreasing ubiquitination level of p53."
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"In contrast to in vivo profiling (Fig. 2) and HNPK keratinocytes at day 12 (Fig. 3 J), cycling HNPK cells of day 3 did not appear to exhibit activation but rather inhibition of a p53-mediated stress response, as seen by lower expression levels of the transcriptional activator of p53, Rarres3, and 30 times–increased levels of Park2, a E3 ubiquitin ligase and transcriptional repressor of p53 (Sunico et al., 2013)."
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"Min et al. showed that one p53 target gene, phosphatase of regenerating liver 1 (PRL-1), that is overexpressed in a variety of cancers through an unknown mechanism, strongly down-regulated p53 levels and inhibited p53 mediated apoptosis by inducing MDM2 phosphorylation through Akt signaling, which forms another feedback loop contributing to HCC development."
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"Consistency with this fact Co O NPs induced apoptosis demonstrated in melanoma A-375 cells can be attributed to the noticed concurrent marked upregulation of Bcl2 gene expression alongside with significant down regulation of p53 and mitochondrial ND3.The downregulation of p53 and ND3 gene expression sets up a cellular environment marked by unchecked DNA damage, impaired mitochondrial function, and increased oxidative stress ."
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"Based on the results, compared with the ART+Vehicle II group, cells in the ART+C646 group exhibited diminished total acetylation and p53 levels (all p<0.05, Fig. 4F), diminished p53 acetylation levels (p<0.01, Fig. 4D), suppressed p53 protein stability (p<0.05, Fig. 4E), and elevated levels of SLC7A11 and GPX4 (all p<0.05, Fig. 4F)."
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"These observations demonstrated that the pulsatile change of both HuR and p53 in response to UV irradiation is abolished with knockdown of TRIM21, hence confirming TRIM21 as the E3 ubiquitin ligase involved in HuR degradation and consequently regulating the pulsatile expression of p53."
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"More research revealed that MC-LR enhanced the levels of the genes p53, p21, and gadd45a, which are downstream regulators of p53 and oversee arresting the cell cycle and reconstruction of DNA, mdm2, a feedback regulator of p53 expression and activity, and the bax/bcl-2 ratio, which triggers apoptosis.mtDNA mutations can arise 10–20 times more frequently than nuclear DNA (nDNA) [101]."
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"Li et al. (76) investigated PURPL, the lncRNA that is regulated by p53, which inhibits basal p53 levels and facilitates tumorigenicity in CRC via associating with MYBBP1A and inhibiting formation of the p53-MYBBP1A complex.Another lncRNA, colon cancer-associated transcript 2 (CCAT2), is an RNA with the length of 1,752 bp located on chromosome 8q24.21."
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"By causing MDM2 phosphorylation via Akt signalling, Minand and colleagues demonstrated that one p53 target gene, phosphatase of regenerating liver 1 (PRL-1), which is overexpressed in a number of cancers via an unknown mechanism, firmly downregulated p53 levels and inhibited p53-mediated apoptosis, forming yet another feedback loop that contributes to HCC development[34]."