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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]."
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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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"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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"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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"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."
"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."
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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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"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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"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."
"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."
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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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"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."
"# 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]"
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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)."
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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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"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."
"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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"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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"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)."
"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."
"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."
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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."
"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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"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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"The p53 specific shRNA reduced p53 levels by 80 to 90%, and these p53 knockdown cells were also significantly less sensitive to both Nutlin-3a and KPT-185 induced apoptosis (i.e., P < 0.05 in drug specific annexin V induction at all concentrations examined, XREF_FIG), suggesting that both the MDM2 inhibitor Nutlin-3a and the XPO1 inhibitor KPT-185 activate p53 mediated signaling to induce apoptosis in MCL cells."
"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"
"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."
"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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"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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"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."
"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."
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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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"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]."