Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents.
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PMID:Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. 1661 62

The BCL6 proto-oncogene encodes a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation, and survival. BCL6 suppresses p53 in GCB-cells and its constitutive expression can protect B-cell lines from apoptosis induced by DNA damage. BCL6-mediated expression may allow GCB-cells to sustain the low levels of physiological DNA breaks related to somatic mutation (SM) and immunoglobulin class switch recombination which physiologically occur in GCB-cells. Three types of genetic events occur in the BCL6 locus and involve invariably the 5' non-coding region and include translocations, deletions and SM actively targeted to the 5' untranslated region. These acquired mutations occur independently of translocations but may be involved in the deregulation of the gene and/or translocation mechanisms. The favorable prognostic value of high levels of BCL6 gene expression in NHL seems well-established. By contrast, the relevance of SM or translocation of the gene remains unclear. However, it is likely that non-Hodgkin's lymphomas (NHL) harboring the most frequent translocation involving BCL6, i.e. t(3;14), are characterized by a common cell of origin and similar oncogenic mechanisms. Several experiments and mouse models mimicking BCL6 translocation occurring in human lymphoma have demonstrated the oncogenic role of BCL6 and constitute a rational to consider BCL6 as a new therapeutic target in NHL. BCL6 blockade can be achieved by different strategies which include siRNA, interference by specific peptides or regulation of BCL6 acetylation by pharmacological agents such as SAHA or niacinamide and would be applicable to most type of B-cell NHL.
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PMID:The BCL6 proto-oncogene: a leading role during germinal center development and lymphomagenesis. 1681 42

Resveratrol is a polyphenolic compound that exhibits anti-proliferative and anti-inflammatory activities. BCL6, a transcriptional repressor frequently translocated in lymphomas, including diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (FL), regulates germinal center B-cell differentiation. We report herein that resveratrol treatment of human LY8 follicular lymphoma cells leads to an accumulation of LY8 cell in G0/G1 phase and apoptosis. Resveratrol decreased the expression of BCL6 protein, concomitant with the increased expression of several BCL6 regulated gene products, including p27, p53 and CD69. In addition, resveratrol reduces Myc expression in LY8 cells. These results demonstrate for the first time that resveratrol inhibits a BCL6-linked pathway and suggest that loss of BCL6 expression may represent a key event underlying the anti-proliferative activities of resveratrol on LY8 cells. The use of resveratrol to treat aggressive lymphomas with BCL6 and/or MYC translocations may prove useful as an effective therapy.
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PMID:Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: evidence for a novel mechanism involving inhibition of BCL6 signaling. 1708 97

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
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PMID:Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. 1762 4

We studied 613 genes which regulate immunity and, utilizing predictive algorithms, identified 285 genes as microRNA (miRNA or miR) targets. Of these, approximately 250 are newly predicted gene-miR interactions. The frequency of predicted miRNA binding sites in immune gene 3'UTRs indicated preferential targeting of immune genes compared to the genome. Major targets include transcription factors, cofactors and chromatin modifiers whereas upstream factors, such as ligands and receptors (cytokines, chemokines and TLRs), were, in general, non-targets. About 10% of the immune genes were 'hubs' with eight or more different miRNAs predicted to target their 3'UTRs. Hubs were focused on certain key immune genes, such as BCL6, SMAD7, BLIMP1, NFAT5, EP300 and others. NF-kappaB and p53 do not themselves have binding sites for miRNAs but rather these pathways are targeted by miRNAs at downstream sites. MHC class II genes lacked miRNA targets but binding sites were identified in the CIITA gene and were shown experimentally to repress IFN-gamma-induced MHC class II activation. Unexpectedly, factors involved in regulating message stability via AU-rich elements (ARE) were heavily targeted. Moreover, multiple components involved in the generation and effector functions of miRNAs (Dicer and Argonautes) were themselves miRNA targets suggesting that a subset of miRNAs may indirectly control their own production as well as other miRNAs.
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PMID:MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. 1806 76

Previously we have reported the presence of simian virus 40 DNA in 56% of diffuse large B-cell lymphomas in Tunisia. Here, we investigated the relationship between the status of simian virus 40 and t(14;18) translocation, germinal center status, and P53 and BCL2 expression to assess the clinical and biological relevance of simian virus 40 presence in diffuse large B-cell lymphomas. Therefore, we evaluated by immunohistochemistry the expression patterns of CD10, BCL6, MUM1, BCL2, and P53 in 86 diffuse large B-cell lymphomas (48 simian virus 40-positive and 38 simian virus 40-negative cases). The t(14;18) translocation was investigated by polymerase chain reaction. Immunostaining patterns for CD10, BCL6, and MUM1 were used to subclassify diffuse large B-cell lymphoma cases as germinal center or non-germinal center phenotypes. Germinal center phenotype, t(14;18), P53, and BCL2 expression were found in 71, 30, 55, and 65% of cases, respectively. Interestingly, germinal center phenotype, t(14;18), and P53 accumulation were found to be more frequent in simian virus 40-positive cases than in simian virus 40-negative ones (81, 44, 69 vs 58, 13, 37%; P=0.018, 0.002, and 0.003, respectively). However, there were no correlations between the presence of simian virus 40 and the expression of CD10, BCL6, MUM1 and BCL2, patient's age and gender, clinical stage, or the International Prognosis Index. Multivariate logistic regression analyses revealed that the germinal center phenotype, P53 accumulation, and t(14;18) were independent factors for simian virus 40 association (P=0.029, 0.006, and 0.014, respectively). There were no significant differences in overall survival regarding P53, BCL2, or t(14;18) status. However, patients with germinal center phenotype or low International Prognosis Index scores displayed a significantly better survival than those with non-germinal center phenotype or high International Prognosis Index scores (P=0.003 and 0.0001, respectively). These two prognosis factors remain independent in multivariate analyses (P=0.001 and <0.0001, respectively). Interestingly, among patients with germinal center phenotype, simian virus 40-positive subgroup displayed a significantly shorter survival than simian virus 40-negative subgroup (P=0.034). In summary, these findings support a role of simian virus 40 in the pathogenesis of diffuse large B-cell lymphomas. On other hand, they suggest that a significant proportion of diffuse large B-cell lymphoma cases with germinal center phenotype may result from early transformation by simian virus 40, mainly those harboring the t(14;18). Modern Pathology (2008) 21, 282-296; doi:10.1038/modpathol.3800993; published online 28 December 2007.
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PMID:Presence of simian virus 40 in diffuse large B-cell lymphomas in Tunisia correlates with germinal center B-cell immunophenotype, t(14;18) translocation, and P53 accumulation. 1816

BCL6 is a transcriptional repressor protein that is expressed in a developmentally regulated fashion during B-cell maturation. Specifically, BCL6 is required for formation of germinal centers in response to T-cell dependent antigen activation. Germinal center B-cells feature the ability to tolerate rapid proliferation and simultaneous genetic recombination. Genetic lesions that cause constitutive expression of BCL6 are commonly associated with diffuse large B-cell lymphomas (DLBCL). Recent studies show that BCL6 contributes to the germinal center phenotype by directly repressing genes involved in sensing or responding to DNA damage including ATR, TP53 and CDKN1A. The CHEK1 protein is activated through phosphorylation by the ATR kinase domain in response to DNA damage. Activated CHEK1 can phosphorylate and modulate the activity a number of proteins including p53, providing a link between ATR sensing of DNA damage and p53 checkpoint activity. Herein we show that BCL6 can directly bind to a DNA consensus element in the CHEK1 promoter and repress its expression in normal and malignant B-cells. DLBCL cells can be killed by a specific BCL6 peptide inhibitor (BPI) that interferes with corepressor binding to the BCL6 BTB domain. BPI could reactivate CHEK1 in DLBCL cells, suggesting that its induction might contribute to BPI anti-lymphoma effects. Therefore, BCL6 can suppress multiple genes involved in a common pathway sensing, transducing and responding to genotoxic stress.
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PMID:BCL6 represses CHEK1 and suppresses DNA damage pathways in normal and malignant B-cells. 1834 18

Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and controls downstream checkpoints, including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small-molecule activators provided a more powerful antilymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy.
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PMID:Sequential transcription factor targeting for diffuse large B-cell lymphomas. 1845 Nov 63

Germinal center (GC) B cells undergo somatic hypermutation, class switch recombination, and rapid clonal expansion to produce high-affinity antibodies. The BCL6 transcriptional repressor facilitates this phenotype because it can repress DNA damage checkpoint genes. GC B and T cells can make transient direct physical contact; T cells were observed to be associated with dead B-cell fragments. We thus hypothesized that one function of CD40 signaling from T cells within this timeframe could be to modulate BCL6 activity. CD40 signaling rapidly disrupts the ability of BCL6 to recruit the SMRT corepressor complex by excluding it from the nucleus, leading to histone acetylation, RNA polymerase II processivity, and activation of BCL6 target genes, such as CD23b, ATR, and TP53. Washout of CD40 to emulate transient T-cell contact permitted BCL6 target gene mRNA levels to return to their repressed levels, demonstrating that this is a reversible process, which could allow centroblasts that pass quality control to either continue proliferation or undergo terminal differentiation. These data suggest that transient CD40 signaling in the GC might allow T cells to weed out heavily damaged centroblasts while at the same time promoting survival of intact B cells, which could undergo differentiation or additional rounds of proliferation.
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PMID:Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells. 1848 9

The BCL6 oncogenic transcriptional repressor is required for development of germinal center centroblasts, which undergo simultaneous genetic recombination and massive clonal expansion. Although BCL6 is required for survival of centroblasts, its expression in earlier B-cells is toxic. Understanding these opposing effects could provide critical insight into normal B-cell biology and lymphomagenesis. We examined the transcriptional and biological effects of BCL6 in various primary cells. BCL6 repression of ATR was previously shown to play a critical role in the centroblast phenotype. Likewise, we found that BCL6 could impose an ATR-dependent phenotype of attenuated DNA damage sensing and repair in primary fibroblasts and B-cells. BCL6 induced true genomic instability because DNA repair was delayed and was qualitatively impaired, which could be critical for BCL6-induced lymphomagenesis. Although BCL6 can directly repress TP53 in centroblasts, BCL6 induced TP53 expression in primary fibroblasts and B-cells, and these cells underwent p53-dependent growth arrest and senescence in the presence of physiological levels of BCL6. This differential ability to trigger a functional p53 response explains at least in part the different biological response to BCL6 expression in centroblasts versus other cells. The data suggest that targeted re-activation of TP53 could be of therapeutic value in centroblast-derived lymphomas.
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PMID:BCL6-mediated attenuation of DNA damage sensing triggers growth arrest and senescence through a p53-dependent pathway in a cell context-dependent manner. 1852 63


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