• Klíčová slova
• Rubinstein-Taybi syndrome, autoimmune lymphoproliferative syndrome, combined immunodeficiency, common variable immunodeficiency, syndromic immunodeficiency,
• MeSH
• lidé MeSH
• missense mutace MeSH
• mladiství MeSH
• protein p300 asociovaný s E1A genetika   MeSH
• Rubinsteinův-Taybiho syndrom komplikace   genetika   MeSH
• těžká kombinovaná imunodeficience etiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• Názvy látek
• EP300 protein, human MeSH Prohlížeč
• protein p300 asociovaný s E1A MeSH

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.

• Klíčová slova
• EP300, acetylation, aging, autophagy, longevity, metabolome, salicylate,
• MeSH
• acetylkoenzym A metabolismus   MeSH
• Aspirin farmakologie   MeSH
• autofagie účinky léků   genetika   MeSH
• kalorická restrikce * MeSH
• lidé MeSH
• metabolom účinky léků   MeSH
• metabolomika MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• protein p300 asociovaný s E1A metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• acetylkoenzym A MeSH
• Aspirin MeSH
• EP300 protein, human MeSH Prohlížeč
• protein p300 asociovaný s E1A MeSH

Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency. However, the mechanism of hepatic Ggt regulation has not been explored fully. In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression of Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model. The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats. Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats. These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.

• MeSH
• acetylace MeSH
• experimentální diabetes mellitus enzymologie   genetika   MeSH
• gama-glutamyltransferasa biosyntéza   genetika   MeSH
• histonacetyltransferasy metabolismus   MeSH
• histony metabolismus   MeSH
• játra enzymologie   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• promotorové oblasti (genetika) MeSH
• protein p300 asociovaný s E1A metabolismus   MeSH
• protein vázající CREB metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CREBBP protein, human MeSH Prohlížeč
• Crebbp protein, rat MeSH Prohlížeč
• Ep300 protein, rat MeSH Prohlížeč
• gama-glutamyltransferasa MeSH
• histonacetyltransferasy MeSH
• histony MeSH
• protein p300 asociovaný s E1A MeSH
• protein vázající CREB MeSH

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

• Klíčová slova
• EP300, EWSR1, FOXO1, Gene fusion, Neuroepithelial tumor, PLAGL1, Supratentorial,
• MeSH
• dítě MeSH
• ependymom genetika   MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   MeSH
• onkogenní fúze MeSH
• proteiny buněčného cyklu genetika   MeSH
• supratentoriální nádory genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• PLAGL1 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• transkripční faktory MeSH

Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.

• Klíčová slova
• AhR, CYP1 enzymes, Cancer cells, Cell proliferation, p300, β-Catenin signaling,
• MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• enzymová indukce fyziologie   MeSH
• HCT116 buňky MeSH
• játra patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory tračníku genetika   patologie   MeSH
• proliferace buněk fyziologie   MeSH
• protein p300 asociovaný s E1A metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální dráha Hippo fyziologie   MeSH
• signální dráha Wnt fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• viabilita buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CYP1A1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• EP300 protein, human MeSH Prohlížeč
• protein p300 asociovaný s E1A MeSH

Histone acetylation modulates alternative splicing of several hundred genes. Here, we tested the role of the histone acetyltransferase p300 in alternative splicing and showed that knockdown of p300 promotes inclusion of the fibronectin (FN1) alternative EDB exon. p300 associates with CRE sites in the promoter via the CREB transcription factor. We created mini-gene reporters driven by an artificial promoter containing CRE sites. Both deletion and mutation of the CRE site affected EDB alternative splicing in the same manner as p300 knockdown. Next we showed that p300 controls histone H4 acetylation along the FN1 gene. Consistently, p300 depletion and CRE deletion/mutation both reduced histone H4 acetylation on mini-gene reporters. Finally, we provide evidence that the effect of CRE inactivation on H4 acetylation and alternative splicing is counteracted by the inhibition of histone deacetylases. Together, these data suggest that histone acetylation could be one of the mechanisms how promoter and promoter binding proteins influence alternative splicing.

• Klíčová slova
• alternative splicing, fibronectin, histone acetylation, p300, promoter,
• MeSH
• acetylace MeSH
• alternativní sestřih * MeSH
• fibronektiny genetika   metabolismus   MeSH
• genový knockdown MeSH
• HeLa buňky MeSH
• histony metabolismus   MeSH
• integrasy genetika   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• protein p300 asociovaný s E1A genetika   metabolismus   MeSH
• reportérové geny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Cre recombinase MeSH Prohlížeč
• EP300 protein, human MeSH Prohlížeč
• fibronektiny MeSH
• FN1 protein, human MeSH Prohlížeč
• histony MeSH
• integrasy MeSH
• messenger RNA MeSH
• protein p300 asociovaný s E1A MeSH

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.

• MeSH
• adenoidně cystický karcinom * genetika   patologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• hybridizace in situ fluorescenční * MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• nádorové biomarkery * genetika   MeSH
• nádory vedlejších dutin nosních * genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory NFI genetika   MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• MYB-NFIB fusion protein, human MeSH Prohlížeč
• nádorové biomarkery * MeSH
• NFIB protein, human MeSH Prohlížeč
• transkripční faktory NFI MeSH

The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode Caenorhabditis elegans. In sum, aspirin acts as a CRM.

• Klíčová slova
• AMPK, Acetylation, aging, autophagy, fasting, inflammation, longevity, mitophagy, salicylate,
• MeSH
• acetylkoenzym A MeSH
• Aspirin MeSH
• autofagie * MeSH
• Caenorhabditis elegans MeSH
• kalorická restrikce * MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylkoenzym A MeSH
• Aspirin MeSH

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

• Klíčová slova
• BCR signaling, Epigenetics, Follicular lymphoma, Transformation, Tumor microenvironment, miRNA,
• MeSH
• biologické markery MeSH
• epigeneze genetická MeSH
• folikulární lymfom etiologie   metabolismus   patologie   MeSH
• lidé MeSH
• nekódující RNA genetika   MeSH
• protoonkogenní proteiny c-bcl-2 genetika   metabolismus   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• nekódující RNA MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• receptory antigenů B-buněk MeSH