Oncogenes in transgenic mice (original) (raw)
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Oncogenes and Tumor Suppressor Genes
Acta Oncologica, 1988
The artificial selection of the directly acting or acute RNA tumor viruses for high transforming ability has led to the isolation of defective retroviral genomes that have picked up, by accidental recombination, some of the important genes that influence, trigger or regulate cell division. These genes belong to at least four functionally different groups. Each of them can contribute to tumor development and/or progression after activation by structural or regulatory changes. Growth factor genes may act as oncogenes following constitutive activation in a cell that normally responds to, but does not produce, the corresponding growth factor (the autocrine model, exemplified by sis). Growth factor receptors may be fixed in a state of continuous, faulty signalling by the truncation of their external, ligand binding portion (examples: erb-B, fms). Genes coding for proteins involved in signal transduction may be activated by point mutations in certain, important domains (example: the ras-family). DNA binding proteins, presumably involved in DNA replication may drive cell division after constitutive activation by retroviral insertion, chromosomal translocation or gene amplification (example: the mycfamily).
Journal of Developmental Biology and Tissue Engineering, 2011
The main goal is connected with providing, on the one hand, of active tumor-suppressor genes for prevention of eventual malignant transformations, and, on the other hand, of functionally active oncogenes for prevention of early aging and death, both in vitro and in vivo. Modulation of an adequate immune control was also necessary, and in this way any eventual unwished side effects from the genetic manipulations applied, could be escaped. Gene transfer in laboratory-cultivated mouse embryonic stem cells (mESCs) was made by use of appropriate recombinant DNA-constructs, which contained the promoter for gene, coding Elongation Factor 1-alpha (EF1-α), isolated from adenoassociated virus (AAV) (Parvoviridae); gene Dcn1, isolated from 3T3 fibroblasts of laboratory mice Balb/c, as well as gene for neomycin resistance, isolated from bacterial DNA-plasmid. Besides those indicated in the scientific literature inactivation of oncogene Dcn1 in the process of normal cell differentiation, its presence in the genome was supported and confirmed by our results from electrophorhesis of genomic DNA from normal mature epithelial cells of adult Balb/c laboratory mice. Furthermore, electrophorhetic profiles of genetic material from wild type (WT) on oncogene Dcn1 and "knock-down" (KD) on it inbred lines experimental mice differed not only on this oncogene, but also on the tumor-suppressor gene HACE1 in both categories of laboratory rodents. Similarly transfected Hela and RIN-5F malignant cells were then in vitro-co-cultivated with myeloid cell precursors, derived from populations of non-transfected laboratory-cultivated mESCs, in the presence of Doxyciclin, known from many literature data as activator of tumor-suppressor genes from STAT-family expression. Our results were also confirmed by the noticed differences in the degree of myeloid differentiation of derived precursor cells in their in vitro-co-cultivation with containing additional copies of tumor-suppressor genes malignant cells from both lines described, in comparison with the data, obtained in their laboratory co-cultivation with non-treated human cervical carcinoma Hela cells. Differences were also observed in in vitro-co-cultivation with the derived by us normal mESCs, containing additional copy of oncogene Dcn1 by the described above transfection with recombinant DNA-constructs. On the other hand, the derived normal cells with inserted additional copy of oncogene Dcn1 have indicated good safety and immunogenity. These cells have also indicated preserved normal cell characteristics, as well as eventual over-expression of the experimentally-activated oncogene Dcn1 in them.
Cell transformation: the role of oncogenes and factors
Mutagenesis, 1986
An attempt is made to draw together diverse areas of biological research which have recently converged and opened up new experimental approaches to understanding the nature of cancer. In particular, the powerful techniques of molecular biology have been brought to bear on tissue culture systems. The case is made for the continued use of cell transformation in vitro as a real and useful model for cancer development. The hallmark of all cancer cells is loss of control over the cell cycle and the cellular elements involved, growth factors, growth factor receptors and signal transducers have been identified and in some instances shown to be encoded in cellular oncogenes. Moreover, as the molecular mechanisms underlying cell growth control are unravelled, those aspects involved in neoplastic change will be identified and this will lead to the development of definitive short-term tests for the detection of chemical carcinogens.
Cell transformation: the role of oncogenes and growth factors
An attempt is made to draw together diverse areas of biological research which have recently converged and opened up new experimental approaches to understanding the nature of cancer. In particular, the powerful techniques of molecular biology have been brought to bear on tissue culture systems. The case is made for the continued use of cell transformation in vitro as a real and useful model for cancer development. The hallmark of all cancer cells is loss of control over the cell cycle and the cellular elements involved, growth factors, growth factor receptors and signal transducers have been identified and in some instances shown to be encoded in cellular oncogenes. Moreover, as the molecular mechanisms underlying cell growth control are unravelled, those aspects involved in neoplastic change will be identified and this will lead to the development of definitive short-term tests for the detection of chemical carcinogens.
Mechanisms of Oncogene Activation
New Aspects in Molecular and Cellular Mechanisms of Human Carcinogenesis, 2016
The main modifications that characterize cancer are represented by alterations in oncogenes, tumor-suppressor genes, and non-coding RNA genes. Most of these alterations are somatic and the process is a multistep one. Tumors often arise from an initial transformed cell, and after subsequent genetic alterations different cytogenetically clones lead to tumor heterogeneity. Oncogenes encode proteins that control cell processes such as proliferation and apoptosis. Among these proteins are transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators. Oncogenes activation by structural alteration (chromosomal rearrangement, gene fusion, mutation, and gene amplification) or epigenetic modification (gene promoter hypomethylation, mi-croRNA expression pattern) confers an increased or a deregulated expression. Therefore, cells with such alterations possess a growth advantage or an increased survival rate. Given the fact that expression profiling of these alterations determines specific signatures associated with tumor classification, diagnosis, staging, prognosis, and response to treatment, it highlights the importance of studying oncogenes activation mechanisms and the great potential that they hold as therapeutic tools in the near future.
Specific patterns of oncogene activation in transplacentally induced tumors
Proceedings of the National Academy of Sciences, 1990
Transplacental exposure of rats to a single dose of the direct acting carcinogen methylnitrosourea (MNU) results in the induction of a variety of neoplasias of neuroectodermal, epithelial, and mesenchymal origin. Molecular analysis of the oncogenes present in these tumors revealed a striking degree of tissue specificity. neu oncogenes were found to be reproducibly activated in tumors derived from the peripheral nervous system (PNS), but not in those arising from the central nervous system (CNS). No ras oncogenes were found in either PNS- or CNS-derived tumors. However, Ha-ras oncogenes were detected in each of three mammary carcinomas and Ki-ras oncogenes were present in each of five kidney mesenchymal tumors. These results illustrate that phenotypic expression of activated oncogenes in vivo is not a random process and suggest that normal developmental programs may play an important role in modulating the activation of specific oncogenes by chemical carcinogens. PCR analysis reveale...