RESUMO
Despite substantial progress in understanding the mechanisms of carcinogenesis and fighting oncology diseases, cancer mortality remains rather high. Therefore, there is a striving to reduce this mortality to the level determined by endogenous biological factors. The review analyzes the mutations that lead to cell malignant transformation and describes the contribution that self-renewal of adult tissues makes to tumorigenesis. Cancer progression is considered as a development of a complicated system where cells mutate, evolve, and are subject to selection. Cancer paradoxes are described in conclusion.
Assuntos
Transformação Celular Neoplásica/genética , Mutagênese , Mutação , Neoplasias/genética , Animais , Transformação Celular Neoplásica/metabolismo , Humanos , Neoplasias/metabolismoRESUMO
The embryonic development and carcinogenesis are controlled by many transcription factors. The regulatory systems involved in embryogenesis of an organ are also involved in the tumor development in the same organ. FOX family proteins are transcription factors, which play a key role in these processes. The pioneering factors of the FOXA subfamily act at the very early stages of the embryonic development by interacting with condensed chromatin and thereby enabling the expression of the formerly silent important transcription factors. The role of these factors in tumor development is currently not fully elucidated, although recent studies indicate the important contribution of the FOXA subfamily proteins at the early stages of carcinogenesis. This review is restricted to the role of the FOXA factors in embryogenesis of the pancreas and their significance in the development of the pancreatic ductal adenocarcinoma.
Assuntos
Transformação Celular Neoplásica , Embrião de Mamíferos , Desenvolvimento Embrionário , Fatores Nucleares de Hepatócito , Proteínas de Neoplasias , Neoplasias Pancreáticas , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Fatores Nucleares de Hepatócito/genética , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologiaRESUMO
The review discusses the causes of multiple failures in cancer treatment, which might primarily result from the excessive variability of cancer genomes. They are capable of changing their spatial and temporal architecture during tumor development. The key reasons of irreproducibility of biomedical data and the presumable means for improvement of therapeutic results aiming at targeting the most stable tumor traits are suggested.
Assuntos
Biologia Molecular , Neoplasias/genética , Animais , Humanos , Neoplasias/patologia , Neoplasias/terapia , Reprodutibilidade dos TestesRESUMO
Histone H2A can deliver transgenic DNA into mammalian cells in vitro. The ability of DNA delivery in vivo is a question of the further work, but it is possible to estimate factors in in vitro experiments, which affect delivery in vivo. The first step in this direction was to determine sizes and ζ-potentials of histone H2A complexes with DNA. In this work, we produced recombinant histone H2A and its modification, containing TAT-peptide from human immunodeficiency virus TAT protein, which is capable of enhancing macromolecule delivery into mammalian cells. The effective diameters and ζ-potentials of histones-DNA complexes were estimated. Complexes of histone H2A and complexes of modified histone H2A-TAT with DNA had positive ζ-potentials. Complexes of histone H2A with DNA had an effective diameter of about 200 nm. Histone modification with TAT-peptide led to aggregation and formation of massive particles of about 1 µm in diameter.
Assuntos
DNA/química , Histonas/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , HIV-1/química , HIV-1/genética , Histonas/genética , Humanos , Tamanho da Partícula , Plasmídeos/química , Plasmídeos/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genéticaRESUMO
Pioneer transcription factors constitute a heterogeneous group of regulatory proteins of animals, which, unlike other transcription factors, are able to recognize and bind target DNA sequences within closed chromatin. This binding can change the local chromatin structure and facilitate binding of other proteins, thus establishing competence for gene expression. The ability to bind silent genes in the closed environment makes the pioneer factors very useful in the processes leading to cardinal alteration of cell phenotype, such as differentiation in embryonic development or cell reprogramming. These proteins can remain bound to target sequences during mitotic division, and due to this probably take part in the maintenance of cellular memory. Apparently, pioneer transcription factors are active participants in carcinogenesis and maintenance of tumor cell phenotype, although their role in these processes needs additional research. It is reasonable to suppose that a further study will help to shed more light on the genetic processes in embryonic development, increase the efficiency of cell reprogramming and also develop new approaches to diagnostics and therapy of cancer diseases.
Assuntos
Montagem e Desmontagem da Cromatina , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias , Neoplasias , Fatores de Transcrição , Animais , Diferenciação Celular/genética , Reprogramação Celular/genética , Cromatina/genética , Cromatina/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Simultaneous expression of multiple target genes is often required in biotechnology. Multicistronic vectors coding for several proteins are being actively developed for this purpose. In commercially available vectors different variants ofencephalomyocarditis virus internal ribosome entry site (IRES EMCV) are used most often. However, many researchers consider that utilization ofself-cleaving 2A peptides sequences within multi- and bicistronic vectors is more promising. In this work, we compared the efficiency of gene expression in cells transfected with bicistronic vectors based on IRES EMCV and 2A peptide sequence derived form porcine teschovirus-1 (P2A). Efficiency ofgene expression was determined in three mammalian cell lines by measurement of co-expression levels of genes coding for RFP and EGFP proteins linked by IRES or P2A sequence. Higher level oftransgene expression was exhibited by cells transfected with the vector containing the 2A peptide sequence.
