BACKGROUND: Cellular transformation induced by oncogenic viruses is a complex process including viral molecules, host cells and environmental factors. Viruses alone are unable to reproduce and thus they need a host to use their signalling, proteosynthetic and metabolic pathways. One target host molecule is the p53 tumour suppressor. Viral proteins functionally inactivate p53 and deregulate the expression of proteins active during apoptosis, cell proliferation and DNA damage response. Hepatitis virus B HbX protein and hepatitis virus C proteins NS2 and NS5A interact with p53 and prevent its localisation to the nucleus and thus reduce its transcriptional activity. Another mechanism lies in elevated p53 degradation caused by the BZLF1 protein of the Epstein-Barr virus, the LANA protein of the Kaposi sarcoma virus and human papilloma virus E6. The Merkel cell polyomavirus large T antigen does not interact directly with p53, however it acts through downregulation of p53 mediated transcription. The tax protein of human T cell lymphotropic virus type 1 modifies p53 posttranslationally and thus blocks its interaction with other factors of transcription machinery. Due to its tumour suppressor function and role in the maintenance of the genome integrity, the p53 protein is one of the best studied proteins. Following this, evolutionary homologues with important developmental functions p63 and p73 are intensively studied as well. Their roles in oncogenesis have not been clarified yet. PURPOSE: This review describes some of their known interactions with oncogenic viral proteins.

• Klíčová slova
• p53, p63, p73, tumorigenesis, viral proteins, viruses,
• MeSH
• interakce hostitele a patogenu * MeSH
• karcinogeneze metabolismus   patologie   MeSH
• lidé MeSH
• multigenová rodina MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory metabolismus   patologie   virologie   MeSH
• onkogenní viry patogenita   MeSH
• virové proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• TP53 protein, human MeSH Prohlížeč
• virové proteiny MeSH

The p53 family of transcription factors plays key roles in development, genome stability, senescence and tumor development, and p53 is the most important tumor suppressor protein in humans. Although intensively investigated for many years, its initial evolutionary history is not yet fully elucidated. Using bioinformatic and structure prediction methods on current databases containing newly-sequenced genomes and transcriptomes, we present a detailed characterization of p53 family homologs in remote members of the Holozoa group, in the unicellular clades Filasterea, Ichthyosporea and Corallochytrea. Moreover, we show that these newly characterized homologous sequences contain domains that can form structures with high similarity to the human p53 family DNA-binding domain, and some also show similarities to the oligomerization and SAM domains. The presence of these remote homologs demonstrates an ancient origin of the p53 protein family.

• Klíčová slova
• Holozoa, evolution, p53, p63, p73,
• MeSH
• databáze genetické MeSH
• Eukaryota klasifikace   genetika   MeSH
• exony MeSH
• fylogeneze MeSH
• interakční proteinové domény a motivy MeSH
• introny MeSH
• konformace proteinů MeSH
• molekulární evoluce * MeSH
• molekulární modely MeSH
• multigenová rodina * MeSH
• nádorový supresorový protein p53 chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH

The p53 family of proteins evolved from a common ancestor into three separate genes encoding proteins that act as transcription factors with distinct cellular roles. Isoforms of each member that lack specific regions or domains are suggested to result from alternative transcription start sites, alternative splicing or alternative translation initiation, and have the potential to exponentially increase the functional repertoire of each gene. However, evidence supporting the presence of individual protein variants at functional levels is often limited and is inferred by mRNA detection using highly sensitive amplification techniques. We provide a critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms. We conclude that despite the wealth of publications, several putative isoforms remain poorly established. Future research with improved technical approaches and the generation of isoform-specific protein detection reagents is required to establish the physiological relevance of p53-family isoforms in health and disease. In addition, our analyses suggest that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.

• MeSH
• alternativní sestřih * MeSH
• lidé MeSH
• messenger RNA metabolismus   genetika   MeSH
• molekulární evoluce MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   MeSH
• počátek transkripce MeSH
• protein - isoformy * genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• messenger RNA MeSH
• nádorový supresorový protein p53 * MeSH
• protein - isoformy * MeSH

BACKGROUND: ΔNp63 overexpression is a common event in squamous cell carcinoma (SCC) that contributes to tumorigenesis, making ΔNp63 a potential target for therapy. METHODS: We created inducible TP63-shRNA cells to study the effects of p63-depletion in SCC cell lines and non-malignant HaCaT keratinocytes. DNA damaging agents, growth factors, signaling pathway inhibitors, histone deacetylase inhibitors, and metabolism-modifying drugs were also investigated for their ability to influence ΔNp63 protein and mRNA levels. RESULTS: HaCaT keratinocytes, FaDu and SCC-25 cells express high levels of ΔNp63. HaCaT and FaDu inducible TP63-shRNA cells showed reduced proliferation after p63 depletion, with greater effects on FaDu than HaCaT cells, compatible with oncogene addiction in SCC. Genotoxic insults and histone deacetylase inhibitors variably reduced ΔNp63 levels in keratinocytes and SCC cells. Growth factors that regulate proliferation/survival of squamous cells (IGF-1, EGF, amphiregulin, KGF, and HGF) and PI3K, mTOR, MAPK/ERK or EGFR inhibitors showed lesser and inconsistent effects, with dual inhibition of PI3K and mTOR or EGFR inhibition selectively reducing ΔNp63 levels in HaCaT cells. In contrast, the antihyperlipidemic drug lovastatin selectively increased ΔNp63 in HaCaT cells. CONCLUSIONS: These data confirm that ΔNp63-positive SCC cells require p63 for continued growth and provide proof of concept that p63 reduction is a therapeutic option for these tumors. Investigations of ΔNp63 regulation identified agent-specific and cell-specific pathways. In particular, dual inhibition of the PI3K and mTOR pathways reduced ΔNp63 more effectively than single pathway inhibition, and broad-spectrum histone deacetylase inhibitors showed a time-dependent biphasic response, with high level downregulation at the transcriptional level within 24 h. In addition to furthering our understanding of ΔNp63 regulation in squamous cells, these data identify novel drug combinations that may be useful for p63-based therapy of SCC.

• Klíčová slova
• DNA damage, Growth factor signaling, Histone deacetylase inhibitors, Oncogene addiction, Squamous cell carcinoma, ΔNp63,
• MeSH
• inhibitory histondeacetylas MeSH
• karcinogeneze MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• nádorový supresorový protein p53 * genetika   MeSH
• rodina MeSH
• spinocelulární karcinom * farmakoterapie   genetika   metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory histondeacetylas MeSH
• nádorové supresorové proteiny MeSH
• nádorový supresorový protein p53 * MeSH
• TP63 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

The effect of mutations in the P53 family of transcription factors on their biological functions, including partial or complete loss of transcriptional activity, has been confirmed several times. At present, P53 family proteins showing partial loss of activity appear to be promising potential candidates for the development of novel therapeutic strategies which could restore their transcriptional activity. In this context, it is important to employ tools to precisely monitor their activity; in relation to this, non-canonical DNA secondary structures in promoters including G-quadruplexes (G4s) were shown to influence the activity of transcription factors. Here, we used a defined yeast assay to evaluate the impact of differently modeled G4 forming sequences on a panel of partial function P53 family mutant proteins. Specifically, a 22-mer G4 prone sequence (derived from the KSHV virus) and five derivatives that progressively mutate characteristic guanine stretches were placed upstream of a minimal promoter, adjacent to a P53 response element in otherwise isogenic yeast luciferase reporter strains. The transactivation ability of cancer-associated P53 (TA-P53α: A161T, R213L, N235S, V272L, R282W, R283C, R337C, R337H, and G360V) or Ectodermal Dyplasia syndromes-related P63 mutant proteins (ΔN-P63α: G134D, G134V and inR155) were tested. Our results show that the presence of G4 forming sequences can increase the transactivation ability of partial function P53 family proteins. These observations are pointing to the importance of DNA structural characteristics for accurate classification of P53 family proteins functionality in the context of the wide variety of TP53 and TP63 germline and somatic mutations.

• Klíčová slova
• G-quadruplex, P53 and P63 mutant proteins, Partial functionality, Protein-DNA interactions, Y1H isogenic system,
• MeSH
• aktivace transkripce MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• mutantní proteiny genetika   MeSH
• nádorový supresorový protein p53 * metabolismus   MeSH
• Saccharomyces cerevisiae genetika   metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• mutantní proteiny MeSH
• nádorový supresorový protein p53 * MeSH
• transkripční faktory MeSH

In last few years, numerous groups of proteins participating in the regulation of cell proliferation, differentiation and death during ontogenesis have been described. In this study we compared the occurrence of Bcl-2, p53 and myc protein families with the level of proliferative activity and apoptosis during development of duodenal epithelium. Paraffin embedded tissues of eight human embryos and foetuses aged from the 6th-18th week of IUD were used. For the detection of apoptotic cells the TUNEL method was performed, the proliferative marker PCNA and all the proteins studied were detected by means of indirect three-step immunohistochemical method. In the 6th and 8th week of intrauterine development we observed isolated TUNEL positive epithelial cells only and this was accompanied by the disperse presence of PCNA as well as by all the studied proteins: Bcl-2, Bax, Bcl-XL, c-myc, N-myc, p53, p63 and p73. In the early foetal period of duodenal development we registered changes in PCNA and TUNEL positivity in accordance with the constitution of the stem cell pool on base of villi, where more numerous Bcl-2 positive cells were also found. The separation of primitive crypts and villi was not accompanied by any differences in distribution of Bax, Bcl-XL, c-myc, N-myc, p63 and p73 proteins between those compartments: all the studied proteins showed dispersed character. P53 rapidly decreased in this period. In the 18th week of intrauterine development the balance between proliferation in crypts and apoptosis of villi epithelium was well established and no p53 positive cells were found. In the presence of Bcl-2, Bax, Bcl-XL, p63 and p73 we did not find any dramatic changes. The myc proteins were restricted within the epithelium of the Lieberkuhn crypts only.

• MeSH
• apoptóza MeSH
• duodenum cytologie   embryologie   metabolismus   MeSH
• embryo savčí metabolismus   MeSH
• epitel embryologie   metabolismus   MeSH
• imunohistochemie MeSH
• lidé MeSH
• nádorový supresorový protein p53 analýza   MeSH
• proliferace buněk MeSH
• protoonkogenní proteiny c-bcl-2 analýza   MeSH
• protoonkogenní proteiny c-myc analýza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• protoonkogenní proteiny c-myc MeSH

P53, P63, and P73 proteins belong to the P53 family of transcription factors, sharing a common gene organization that, from the P1 and P2 promoters, produces two groups of mRNAs encoding proteins with different N-terminal regions; moreover, alternative splicing events at C-terminus further contribute to the generation of multiple isoforms. P53 family proteins can influence a plethora of cellular pathways mainly through the direct binding to specific DNA sequences known as response elements (REs), and the transactivation of the corresponding target genes. However, the transcriptional activation by P53 family members can be regulated at multiple levels, including the DNA topology at responsive promoters. Here, by using a yeast-based functional assay, we evaluated the influence that a G-quadruplex (G4) prone sequence adjacent to the p53 RE derived from the apoptotic PUMA target gene can exert on the transactivation potential of full-length and N-terminal truncated P53 family α isoforms (wild-type and mutant). Our results show that the presence of a G4 prone sequence upstream or downstream of the P53 RE leads to significant changes in the relative activity of P53 family proteins, emphasizing the potential role of structural DNA features as modifiers of P53 family functions at target promoter sites.

• Klíčová slova
• G-quadruplex (G4) prone sequence, P53 family, transactivation potential, wild-type and mutant P53/P63 proteins, yeast,
• MeSH
• apoptóza genetika   MeSH
• DNA genetika   ultrastruktura   MeSH
• G-kvadruplexy * MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• membránové proteiny genetika   ultrastruktura   MeSH
• nádorový supresorový protein p53 genetika   ultrastruktura   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein p73 genetika   ultrastruktura   MeSH
• proteiny regulující apoptózu genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• responzivní elementy genetika   MeSH
• Saccharomyces cerevisiae genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BBC3 protein, human MeSH Prohlížeč
• CKAP4 protein, human MeSH Prohlížeč
• DNA MeSH
• membránové proteiny MeSH
• nádorový supresorový protein p53 MeSH
• protein p73 MeSH
• proteiny regulující apoptózu MeSH
• protoonkogenní proteiny MeSH
• TP73 protein, human MeSH Prohlížeč

The molecular basis for the transition of carcinoma of the prostate from androgen-dependent to androgen-independent growth is largely unknown. Currently for example, it is not clear whether the androgen-independent phenotype is a result of selection of a subgroup of genetically distinct prostate tumour cells which are already hormone-resistant or a genetic adaptation of prostate tumour cells to the hormone therapy itself. It has also been established that prostate tumour transformation is a result of homeostatic control defects, a line of thinking directed toward elucidating the apoptotic profile of prostate tumour cells that may be important in determining prognosis, response to therapy and illness progression. Main consideration in this part of rewiev is given to the role of Bcl-2 and members of the Bcl-2 family, and tumour suppressor gene p53.

• MeSH
• androgeny * MeSH
• apoptóza fyziologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 fyziologie   MeSH
• nádory prostaty patologie   patofyziologie   MeSH
• nádory závislé na hormonech patologie   patofyziologie   MeSH
• protoonkogenní proteiny c-bcl-2 fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• androgeny * MeSH
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH

Expression of suppressor genes 53 and bcl-2 as well as of protein p21 (partly induced by p53 gene) was analyzed in a group of 77 resection specimens and bronchial excision of lung carcinomas (of all basic histological types--squamous cell, neuroendocrine, adenocarcinoma, undifferentiated). Simultaneously the relation of tumor immunophenotype and level of differentiation, cell death and 2-year-survival of patients was evaluated. Gene p53 showed non-only an expected strong expression in squamous cell carcinomas but especially in adenocarcinomas, which were newly characterized by exceptional hyper-expression of p53 in lowly differentiated variants. Expression level of protein p21 and gene p53 was parallel only in adenocarcinomas and undifferentiated carcinomas but discordant in squamous cell and neuroendocrine carcinomas. Positivity of p21 slightly prevailed in well-differentiated variants of the histological types but an exceptional positivity was found even in all the undifferentiated carcinomas. Gene bcl-2 revealed a paradox of strong expression in lowly differentiated neuroendocrine and undifferentiated carcinomas. The level of bcl-2 expression in squamous cell carcinomas was found higher than in references. Among tumors with cell death there was an inverted relation of bcl-2 and p53 expression (high/low) in neuroendocrine carcinomas but both of them were mostly negative in squamous cell carcinomas. A more frequent 2-year-survival of squamous cell carcinomas was verified for bcl-2 positive tumors and newly for p53 positive squamous cell carcinomas. Evaluation of the expression of p53, p21 and bcl-2 in lung carcinomas is so equivocal that its prognostic usage was found to be only complementary to the direct immunohistochemical investigation of the growth activities.

• MeSH
• imunohistochemie MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• nádorový supresorový protein p53 analýza   MeSH
• nádory plic diagnóza   genetika   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-bcl-2 analýza   MeSH
• protoonkogenní proteiny p21(ras) analýza   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• HRAS protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• protoonkogenní proteiny p21(ras) MeSH

Homeostasis and development in vertebrates are regulated by cell proliferation, differentiation and death. Permeability of mitochondrial membranes, a decisive feature of apoptosis, is regulated by Bcl-2 family regulators. Protein p53 is able to reduce bcl-2 and promote bax expression. This study focused on the immunohistochemical detection of the expression levels of Bcl-2 family regulators (anti-apoptotic Bcl-2 and Bcl-XL, pro-apoptotic Bcl-Xs and Bax), p53, and PCNA as a marker of proliferation, together with the evaluation of the level of apoptosis in human embryos (anlage of limbs, axial skeleton, metanephros, and intestine). Expression of observed proteins was assessed by a three-step immunohistochemistry and evidenced by the double-staining technique. Apoptosis was detected by the TUNEL technique. This study provided circumstantial evidence of the exclusive role of Bcl-2 and Bcl-XL proteins in the inhibition of apoptosis - only rarely were the Bcl-2/ Bcl-XL positive cells stained by TUNEL. The role of pro-apoptotic members of Bcl-2 family remains ambiguous, as TUNEL positive cells are both Bax/Bcl-Xs positive and negative. This study provided substantial evidence that expression patterns of observed proteins are neither fully explainable by "rheostat" theory, nor are the findings obtained from animal model tissue or cell culture commonly applicable to human embryos.

• MeSH
• apoptóza fyziologie   MeSH
• embryo savčí embryologie   metabolismus   MeSH
• embryonální vývoj fyziologie   MeSH
• končetiny embryologie   fyziologie   MeSH
• kosti a kostní tkáň embryologie   metabolismus   MeSH
• ledviny embryologie   metabolismus   MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• orgánová specificita MeSH
• proliferace buněk MeSH
• proliferační antigen buněčného jádra metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• střeva embryologie   MeSH
• střevní sliznice metabolismus   MeSH
• tkáňová distribuce MeSH
• vývojová regulace genové exprese fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• proliferační antigen buněčného jádra MeSH
• protoonkogenní proteiny c-bcl-2 MeSH