Protein p73 is a member of the p53 protein family that can induce cell cycle arrest or apoptosis by the activation of p53-responsive genes as well as p53-independent pathways. Alternative promoter usage, together with differential splicing of the C-terminal exons, forms several distinct mRNAs that are translated into corresponding protein isoforms containing different domains. While TAp73 isoforms respond to genotoxic stress in a manner similar to tumor suppressor p53, ΔTAp73 isoforms inhibit apoptosis during normal development and in cancer cell lines. Thus, the impact of p73 on tumorigenesis depends on a subtle balance between tumor-promoting and -suppressing isoforms. Due to the structural homology between p53 and p73, a subtle balance among p53 family members and their isoforms could influence glioma cell evolution toward malignancy. Thus, the p73 status has to be considered when studying the regulatory role of p53 protein in gliomagenesis. The presented review summarizes recent knowledge about the issue of p73 and its isoforms with respect to neuro-oncology research.

• Klíčová slova
• TP73 gene, gliomagenesis, isoforms, p73 protein,
• MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• genetická transkripce MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorová transformace buněk genetika   metabolismus   MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory centrálního nervového systému genetika   metabolismus   MeSH
• protein - isoformy genetika   MeSH
• protein p73 MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein - isoformy MeSH
• protein p73 MeSH
• TP73 protein, human MeSH Prohlížeč

Epigenetic changes are considered to be a frequent event during tumour development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumour suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in samples of sinonasal carcinoma by comparison with normal sinonasal tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to compare the methylation status of 64 tissue samples of sinonasal carcinomas with 19 control samples. We also compared the human papilloma virus (HPV) status with DNA methylation. Using a 20% cut-off for methylation, we observed significantly higher methylation in RASSF1, CDH13, ESR1 and TP73 genes in the sinonasal cancer group compared with the control group. HPV positivity was found in 15/64 (23.4 %) of all samples in the carcinoma group and in no sample in the control group. No correlation was found between DNA methylation and HPV status. In conclusion, our study showed that there are significant differences in promoter methylation in the RASSF1, ESR 1, TP73 and CDH13 genes between sinonasal carcinoma and normal sinonasal tissue, suggesting the importance of epigenetic changes in these genes in carcinogenesis of the sinonasal area. These findings could be used as prognostic factors and may have implications for future individualised therapies based on epigenetic changes.

• MeSH
• aktivace enzymů MeSH
• dlaždicobuněčné karcinomy hlavy a krku MeSH
• DNA-(cytosin-5-)methyltransferasa genetika   metabolismus   MeSH
• DNA-(cytosin-5)-methyltransferasa 1 MeSH
• epigenomika MeSH
• kadheriny genetika   metabolismus   MeSH
• lidé MeSH
• metylace DNA * MeSH
• nádory hlavy a krku diagnóza   genetika   patofyziologie   virologie   MeSH
• Papillomaviridae izolace a purifikace   MeSH
• prognóza MeSH
• promotorové oblasti (genetika) genetika   MeSH
• spinocelulární karcinom diagnóza   genetika   patofyziologie   virologie   MeSH
• tumor supresorové geny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-(cytosin-5-)methyltransferasa MeSH
• DNA-(cytosin-5)-methyltransferasa 1 MeSH
• H-cadherin MeSH Prohlížeč
• kadheriny MeSH

The recently cloned gene p73 is a close homologue of p53, which is a crucial tumor suppressor gene for preventing the malignant transformation of cells by inducing cell cycle arrest and apoptosis. Previous reports have shown that architectural DNA-bending/looping chromosomal proteins HMGB1 and HMGB2 (formerly known as HMG1 and HMG2), which function in a number of biological processes including transcription and DNA repair, interact in vitro with p53 and stimulate p53 binding to DNA containing p53 consensus sites. Here, we report that HMGB1 physically interacts with two splicing variants of p73, alpha and beta (pull-down assay), and enhances binding of p73 to specific cognate DNA sites (gel-shift assay). Both HMG box domains of HMGB1, A and B, interact with p73alpha. Association of HMGB1 with p73, like the demonstrated ability of HMGB1 to stimulate p73 binding to different p53-responsive elements, requires the oligomerization region and/or region between DNA-binding domain and oligomerization domain of p73 (residues 312-381). Transient transfections revealed that ectopically expressed or endogenous HMGB1 and HMGB2 (antisense strategy) significantly inhibit in vivo both p73alpha/beta- and p53-dependent transactivation from the Bax gene promoter (and much less from Mdm2 and p21(waf1) promoters) in p53-deficient SAOS-2 cells. In contrast, HMGB1 and HGMB2 stimulate p73- or p53-dependent transactivation in p53-deficient H1299 cells, irrespective of the promoter used. Our results suggest that ubiquitously expressed HMGB1 and HMGB2 have potential to cell- and promoter-specifically down- or up-regulate in vivo transcriptional activity of different members of the p53 family. A possible mechanism of HMGB1-mediated modulation of p73- and p53-dependent transactivation is discussed.

• MeSH
• aktivace transkripce * MeSH
• alternativní sestřih MeSH
• buněčné linie MeSH
• DNA vazebné proteiny chemie   genetika   MeSH
• down regulace * MeSH
• geny p53 genetika   MeSH
• glutathiontransferasa metabolismus   MeSH
• jaderné proteiny chemie   genetika   MeSH
• lidé MeSH
• luciferasy metabolismus   MeSH
• nádorové supresorové proteiny MeSH
• plazmidy metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• protein HMGB1 metabolismus   MeSH
• protein HMGB2 metabolismus   MeSH
• protein p73 MeSH
• protein X asociovaný s bcl-2 MeSH
• proteosyntéza MeSH
• protoonkogenní proteiny c-bcl-2 * MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• terciární struktura proteinů MeSH
• transfekce MeSH
• transkripční faktor Sp1 metabolismus   MeSH
• tumor supresorové geny MeSH
• upregulace MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BAX protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• glutathiontransferasa MeSH
• jaderné proteiny MeSH
• luciferasy MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorové supresorové proteiny MeSH
• protein HMGB1 MeSH
• protein HMGB2 MeSH
• protein p73 MeSH
• protein X asociovaný s bcl-2 MeSH
• protoonkogenní proteiny c-bcl-2 * MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• protoonkogenní proteiny MeSH
• TP73 protein, human MeSH Prohlížeč
• transkripční faktor Sp1 MeSH

p73, a member of the p53 family, exhibits activities similar to those of p53, including the ability to induce growth arrest and apoptosis. p73 influences chemotherapeutic responses in human cancer patients, in association with p53. Alternative splicing of the TP73 gene produces many p73 C- and N-terminal isoforms, which vary in their transcriptional activity towards p53-responsive promoters. In this paper, we show that the C-terminal spliced isoforms of the p73 protein differ in their DNA-binding capacity, but this is not an accurate predictor of transcriptional activity. In different p53-null cell lines, p73beta induces either mitochondrial-associated or death receptor-mediated apoptosis, and these differences are reflected in different gene expression profiles. In addition, p73 induces cell cycle arrest and p21(WAF1) expression in H1299 cells, but not in Saos-2. This data shows that TAp73 isoforms act differently depending on the tumour cell background, and have important implications for p73-mediated therapeutic responses in individual human cancer patients.

• MeSH
• aktivace transkripce MeSH
• alternativní sestřih MeSH
• apoptóza fyziologie   MeSH
• buněčné linie MeSH
• buněčný cyklus fyziologie   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• genetická transkripce MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• protein - isoformy genetika   metabolismus   MeSH
• protein p73 MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce fyziologie   MeSH
• stanovení celkové genové exprese MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• transkripční faktory MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein - isoformy MeSH
• protein p73 MeSH
• TP53 protein, human MeSH Prohlížeč
• TP63 protein, human MeSH Prohlížeč
• TP73 protein, human MeSH Prohlížeč
• trans-aktivátory MeSH
• transkripční faktory MeSH

The TP73 gene is a member of the p53 family and through differential promoter usage and alternative splicing can encode a number of different isoforms that have distinct properties. p73 proteins are widely expressed in neural, epithelial, and hemopoietic cells and are proposed to have roles in the development and differentiation of various cell types and in tumorigenesis. The authors have developed a novel monoclonal antibody that is specific for p73alpha to study the expression of this individual isoform in normal and neoplastic cervical epithelium. In normal epithelium, p73alpha is restricted to nonproliferating cells at the base of the epithelium, whereas other p73 isoforms are found in the proliferative zones higher up in the epithelium. In cervical cancers, p73alpha expression is commonly lost, although other p73 isoforms are present at high levels. In particular, the authors found that invasive islands lose p73alpha expression when compared with the overlying intraepithelial lesion. These results show a tight regulation of p73 isoform expression in cervical epithelium and imply that different isoforms of p73 enhance or suppress neoplastic cell growth. These data raise the possibility that reactivation of p73alpha might be beneficial in cervical carcinoma. In addition, the absence of p73alpha in cervical cancer represents a potentially useful tool for the diagnosis of this disease.

• MeSH
• cervix uteri chemie   MeSH
• DNA vazebné proteiny analýza   imunologie   MeSH
• dysplazie děložního hrdla chemie   patologie   MeSH
• epitel chemie   patologie   MeSH
• imunohistochemie MeSH
• jaderné proteiny analýza   imunologie   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádorové biomarkery analýza   imunologie   MeSH
• nádorové supresorové proteiny MeSH
• nádory děložního čípku chemie   patologie   MeSH
• protein - isoformy MeSH
• protein p73 MeSH
• regulace genové exprese u nádorů MeSH
• spinocelulární karcinom chemie   patologie   MeSH
• tumor supresorové geny MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• monoklonální protilátky MeSH
• nádorové biomarkery MeSH
• nádorové supresorové proteiny MeSH
• protein - isoformy MeSH
• protein p73 MeSH
• TP73 protein, human MeSH Prohlížeč

p63 and p73, the two other members of the p53 family, were identified almost 15 years ago. Here, we review their potential use for diagnosis, prognosis and prediction of response to therapy in various cancers. The two genes show distinct expression patterns in both normal and cancer tissues and each gene gives rise to multiple protein isoforms with different activities, including those with tumour-suppressor or oncogenic effects. Despite such complexity, some common themes emerge; p63 is commonly overexpressed as the ΔNp63 isoform and sometimes associated with TP63 amplification, whereas p73 is often reduced (by methylation or gene loss), or there is an increase in the ratio of ΔNp73 to TAp73. These generalisations do not apply universally; TAp63 is overexpressed in haematological malignancies, TP63 mis-sense mutations have been reported in squamous cancers and TP63 translocations occur in lymphomas and some lung adenocarcinomas. There are associations with disease prognosis and response to specific therapies in individual cancer types for both p63 and p73, making their analysis of clinical relevance. We also discuss their utility for aiding in differential diagnosis, which has been demonstrated for p63, but not yet for p73. Throughout, we highlight the discrepant nature of many studies due to the variable methodologies employed, the lack of systematic evaluation of isoforms and the problems of poor antibody characterization and cross-reactions within the p63/p73 family. Finally, we emphasize the value of recently developed isoform-specific reagents that have clear advantages for the study of p63 and p73 experimentally and clinically.

• MeSH
• bodová mutace MeSH
• DNA vazebné proteiny genetika   fyziologie   MeSH
• jaderné proteiny genetika   fyziologie   MeSH
• karcinogeneze MeSH
• lidé MeSH
• modely genetické MeSH
• mutace MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové supresorové proteiny genetika   fyziologie   MeSH
• nádory genetika   metabolismus   MeSH
• onkogeny MeSH
• proliferace buněk MeSH
• protein p73 MeSH
• regulace genové exprese u nádorů * MeSH
• transkripční faktory genetika   fyziologie   MeSH
• tumor supresorové geny MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• delta Np73 protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• nádorové biomarkery MeSH
• nádorové supresorové proteiny MeSH
• protein p73 MeSH
• TP63 protein, human MeSH Prohlížeč
• TP73 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.

• Klíčová slova
• Cervical cancer, Endometrium, Fallopian tube, Multiciliated cells, Squamous epithelial stem cells, p73 isoforms,
• MeSH
• epitelové buňky metabolismus   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádorové buněčné linie MeSH
• nádory děložního čípku metabolismus   patologie   genetika   MeSH
• nádory metabolismus   patologie   genetika   MeSH
• protein - isoformy * metabolismus   genetika   MeSH
• protein p73 * metabolismus   genetika   MeSH
• spinocelulární karcinom metabolismus   patologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• delta Np73 protein, human MeSH Prohlížeč
• monoklonální protilátky MeSH
• protein - isoformy * MeSH
• protein p73 * MeSH
• TP73 protein, human MeSH Prohlížeč

• MeSH
• DNA vazebné proteiny imunologie   MeSH
• hybridomy MeSH
• jaderné proteiny imunologie   MeSH
• lidé MeSH
• monoklonální protilátky imunologie   MeSH
• myši MeSH
• nádorové supresorové proteiny imunologie   MeSH
• nádorový supresorový protein p53 genetika   imunologie   MeSH
• protein p73 MeSH
• protilátky nádorové imunologie   MeSH
• tumor supresorové geny MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• jaderné proteiny MeSH
• monoklonální protilátky MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein p73 MeSH
• protilátky nádorové MeSH
• TP73 protein, human MeSH Prohlížeč
• Trp73 protein, mouse MeSH Prohlížeč

We studied p53, p63, p73 protein expression in the orofacial region of five human embryos aged 7-18 weeks of intrauterine development using a three-step immunohistochemical method. Expression of proteins in various locations was evaluated semiquantitatively. A decrease in p53, p63 and p73 proteins occurred in the 13-week-old material with the exception of the tooth germ where a drop in p73 appeared in the ninth week.

• MeSH
• DNA vazebné proteiny analýza   MeSH
• embryo savčí chemie   MeSH
• fosfoproteiny analýza   MeSH
• imunohistochemie MeSH
• jaderné proteiny analýza   MeSH
• lidé MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 analýza   MeSH
• obličej embryologie   MeSH
• protein p73 MeSH
• trans-aktivátory analýza   MeSH
• transkripční faktory MeSH
• tumor supresorové geny MeSH
• ústa embryologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• fosfoproteiny MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein p73 MeSH
• TP63 protein, human MeSH Prohlížeč
• TP73 protein, human MeSH Prohlížeč
• trans-aktivátory MeSH
• transkripční faktory MeSH

TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.

• Klíčová slova
• Anticancer therapy, Carbaldehydic xanthone, p73,
• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buňky HT-29 MeSH
• cisplatina farmakologie   MeSH
• doxorubicin farmakologie   MeSH
• HCT116 buňky MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• neuroblastom farmakoterapie   genetika   metabolismus   patologie   MeSH
• protein p73 genetika   metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce účinky léků   MeSH
• synergismus léků MeSH
• xantony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• cisplatina MeSH
• doxorubicin MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protein p73 MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• TP53 protein, human MeSH Prohlížeč
• TP73 protein, human MeSH Prohlížeč
• xantony MeSH