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International Journal of Cell Cloning Jan 1988Eukaryotic cells contain a family of genes termed "cellular oncogenes" or "proto-oncogenes," thought to regulate normal cell growth and development. In some... (Review)
Review
Eukaryotic cells contain a family of genes termed "cellular oncogenes" or "proto-oncogenes," thought to regulate normal cell growth and development. In some circumstances, such as following transduction by retroviruses, activation of these genes causes tumors and leukemias in animals. Possible mechanisms of cellular oncogene activation include: 1) DNA point mutation, deletion or insertion, 2) gene amplification, 3) gene activation by internal rearrangement, chromosomal translocation or promoter insertion, 4) recombinative events resulting in the formation of novel chimeric genes, and others. In this review, we consider data which implicates cellular oncogene activation in the pathogenesis of leukemia in humans. We discuss possible mechanisms by which oncogene activation may induce leukemias, as well as potential diagnostic and therapeutic implications.
Topics: Animals; DNA; Humans; Leukemia; Proto-Oncogene Proteins; Proto-Oncogenes; RNA
PubMed: 2448394
DOI: 10.1002/stem.5530060103 -
Environmental Health Perspectives Nov 1992The accumulation of genetic damage in the forms of activated proto-oncogenes and inactivated tumor-suppressor genes is the driving force in the evolution of a normal... (Review)
Review
The accumulation of genetic damage in the forms of activated proto-oncogenes and inactivated tumor-suppressor genes is the driving force in the evolution of a normal cell to a malignant cell. For example, both the activation of ras oncogenes and the inactivation of several suppressor genes, including p53, have been observed in the development of human colon and lung tumors. Point mutations in key codons can activate ras proto-oncogenes and inactivate the p53 suppressor gene. Thus, several critical genes for tumorigenesis are potential targets for carcinogens and radiation that can induce point mutations at low doses. The ras proto-oncogenes are targets for many genotoxic carcinogens. Activation of the ras gene is an early event--probably the "initiating" step--in the development of many chemical-induced rodent tumors. ras Oncogenes are observed in more human tumors and at a higher frequency than any other oncogene, and activation of the proto-oncogene may occur at various stages of the carcinogenic process. Numerous proto-oncogenes other than the ras genes have been shown to be activated in human tumors and to a lesser extent in rodent tumors. Mechanisms that induce aberrant expression of proto-oncogenes are gene amplification and chromosomal translocation or gene rearrangement. Amplification of proto-oncogenes and possibly gene overexpression during the absence of gene amplification occur in the development of many human tumors. For a specific tumor type, amplification of any one proto-oncogene may occur at a low frequency, but the frequency of tumors in which at least one proto-oncogene is amplified can be much higher. Proto-oncogene amplification is usually associated with late stages of tumor progression; however, amplified HER2/neu has been observed in early clinical stages of mammary neoplasia. Activation of proto-oncogenes by chromosomal translocation has been detected at a high frequency in several hematopoietic tumors. Non-ras genes have been detected by DNA transfection assays in both human and rodent tumors. For example, ret and trk genes were found to be activated by gene rearrangements in human papillary thyroid carcinomas. Several potentially new types of oncogenes have also been detected by DNA transfection assays. The etiology of the genetic alterations observed in most human tumors is unclear at present. Examples of ras gene activation and those documented for mutations in the p53 gene demonstrate that exogenous conditions can induce oncogenic mutants of normal genes. The genetic alterations observed in most human tumors are probably generated by both spontaneous events and exogenous conditions.
Topics: Animals; Female; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Mice; Neoplasms; Neoplasms, Experimental; Proto-Oncogene Mas; Proto-Oncogenes; Rats; Transcriptional Activation
PubMed: 1486840
DOI: 10.1289/ehp.929813 -
International Journal of Molecular... Apr 2022The () is proto-oncogene that is classified as a member of the transcription factor family, which has been found to be consistently overexpressed in about half of the... (Review)
Review
The () is proto-oncogene that is classified as a member of the transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of can mostly be attributed to the fusion of the and () genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG's molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. has also been implicated in the epithelial-mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.
Topics: Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Male; Oncogene Proteins, Fusion; Prostatic Neoplasms; Proto-Oncogene Proteins c-ets; Proto-Oncogenes; Transcriptional Regulator ERG
PubMed: 35563163
DOI: 10.3390/ijms23094772 -
Endocrinology and Metabolism (Seoul,... Mar 2019The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of... (Review)
Review
The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting and proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 () and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase () promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the -driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of -driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic -driven thyroid cancers.
Topics: Animals; Carcinoma, Papillary; Class I Phosphatidylinositol 3-Kinases; Disease Progression; High-Throughput Nucleotide Sequencing; Humans; Mice; Mice, Transgenic; Mutation; Promoter Regions, Genetic; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogenes; Telomerase; Thyroid Neoplasms; Tumor Suppressor Protein p53
PubMed: 30784243
DOI: 10.3803/EnM.2019.34.1.11 -
BMC Medical Genomics Nov 2023Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study...
BACKGROUND
Chronic inflammation causes bone destruction in middle ear cholesteatomas (MECs). However, the causes of their neoplastic features remain unknown. The present study demonstrated for the first time that neoplastic features of MEC are based on proto-oncogene mutations.
RESULTS
DNA was extracted from MEC and blood samples of five patients to detect somatic mutations using depth-depth exome sequencing. Exons with somatic variants were analyzed using an additional 17 MEC/blood test pairs. Variants detected in MECs but not in blood were considered pathogenic variant candidates. We analyzed the correlation between proto-oncogene (NOTCH1 and MYC) variants and the presence of bone destruction and granulation tissue formation. MYC and NOTCH1 variants were detected in two and five of the 22 samples, respectively. Two of the NOTCH1 variants were located in its specific functional domain, one was truncating and the other was a splice donor site variant. Mutations of the two genes in attic cholesteatomas (n = 14) were significantly related with bone destruction (p = 0.0148) but not with granulation tissue formation (p = 0.399).
CONCLUSIONS
This is the first study to demonstrate a relationship between neoplastic features of MEC and proto-oncogene mutations.
Topics: Humans; Cholesteatoma, Middle Ear; Ear, Middle; Mutation; Proto-Oncogenes
PubMed: 37968650
DOI: 10.1186/s12920-023-01640-6 -
Scandinavian Journal of Work,... 1992It seems increasingly likely that an important mechanism of action of certain workplace carcinogens in contributing to occupational carcinogenesis may be via the... (Review)
Review
It seems increasingly likely that an important mechanism of action of certain workplace carcinogens in contributing to occupational carcinogenesis may be via the activation of cellular oncogenes, which then cause an expression of mutated forms or increased amounts of their oncoprotein products. Two prototypical models of this mechanism may be the ras oncogene and its p21 protein and the neu oncogene and its p185 protein. Both are known to be activated by exposure to common occupational carcinogens, and both are known to occur frequently in human tumors, including those of occupational concern such as lung cancer. Knowledge of their mechanisms of action may lead to new opportunities for preventing occupational cancer.
Topics: Animals; Genes, ras; Humans; Neoplasms; Occupational Diseases; Oncogene Protein p21(ras); Oncogenes; Proto-Oncogene Proteins; Proto-Oncogenes; Receptor, ErbB-2; Retroviridae
PubMed: 1357742
DOI: No ID Found -
Environmental Health Perspectives Jun 1991Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also... (Review)
Review
Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also involved in some cases of human cancer caused by exposure to nonionizing radiation and may play a mechanistic role in the phenomenon of radioresistance seen in later stages of tumor progression. The mechanisms of oncogene activation seen in radiation-induced tumors include point mutations, gene amplification, and changes in gene expression. Genetic factors associated with target species, strain, and tissue type play an important role in determining the specific nature of oncogene activation by radiation exposure. Using the rat skin as a model for cancer induction by ionizing radiation, we found concurrent activation of K-ras and c-myc oncogenes in end-stage tumors. Amplification of the myc gene proved to occur during a late stage of tumor progression and is not an early initiating event resulting from the direct action of radiation on target cells. The importance of tissue specificity, tumor cell heterogeneity, and physical characteristics of the radiation exposure are discussed.
Topics: Animals; Cell Transformation, Neoplastic; DNA Damage; Gene Amplification; Gene Expression Regulation, Neoplastic; Genes, myc; Genes, ras; Genetic Predisposition to Disease; Humans; Male; Mice; Mice, Inbred Strains; Neoplasms; Neoplasms, Radiation-Induced; Oncogenes; Organ Specificity; Proto-Oncogenes; Radiation Tolerance; Rats; Skin Neoplasms; Xeroderma Pigmentosum
PubMed: 1773800
DOI: 10.1289/ehp.919345 -
The Journal of Investigative Dermatology Oct 1991Psoriasis is a common, sometimes severe, non-malignant skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. Because...
Psoriasis is a common, sometimes severe, non-malignant skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. Because proto-oncogenes are implicated in both cell proliferation and differentiation, their expression could be modified in skin diseases such as psoriasis. The c-fos and c-jun proto-oncogenes, whose products associate to form a heterodimeric transcription factor, are among the first genes to be expressed when certain cells are stimulated to either proliferate or differentiate. Recent studies in our laboratory have shown that the c-fos proto-oncogene is highly expressed in normal human adult skin. In the present study, we used in situ hybridization with RNA to compare the expression and localization of c-fos and c-jun transcripts in 15 lesional and non-lesional psoriatic skin samples. Two clinical variants of psoriasis were studied: the most severe and chronic form or plaque-type psoriasis (N = 10) and rapidly resolutive guttate-type psoriasis (N = 5). Quantitative analysis was performed using a semi-automatic image analyzer and the "Starwise grain" software program. Our control samples included 10 normal skins and eight specimens from other benign hyperproliferative non-psoriatic skin diseases, consisting of three with inflammation (seborrheic dermatitis and atopic dermatitis), and 5 without inflammation (seborrheic keratoses). Control genes we used for in situ hybridization and RNA integrity were keratin 14, which is expressed in the epidermis and was normally expressed in all tissue analyzed, and ribosomal RNA. Our data showed that c-fos and c-jun were expressed to an equivalent extent, both spatially and quantitatively, in all specimens tested. Expression was significantly decreased in plaque-type but not in guttate-type psoriasis. It was also decreased in the three other benign inflammatory cutaneous hyperproliferative disorders, but not in the five non-inflammatory cases. These results were surprising because hyperproliferation was here associated with a decrease in proto-oncogene expression, thus suggesting that c-fos and c-jun do not play a crucial role in the control of keratinocyte proliferation in vivo. However, their reduced expression in some abnormally differentiated skins indicates that both c-fos and c-jun proto-oncogenes may play a key role in keratinocyte differentiation. Their altered expression correlated with severity of the disease and the presence of an inflammatory infiltrate. These data offer a new insight into the role and regulation of these proto-oncogenes in vivo in humans.
Topics: Chronic Disease; Genes, fos; Genes, jun; Humans; Nucleic Acid Hybridization; Proto-Oncogene Mas; Psoriasis; Skin Diseases; Transcription, Genetic
PubMed: 1940437
DOI: 10.1111/1523-1747.ep12483807 -
Cell Feb 2016Mouse embryonic stem cells (mESCs) are capable of unlimited proliferation without losing pluripotency. Scognamiglio et al. now reveal that Myc depletion shifts mESCs...
Mouse embryonic stem cells (mESCs) are capable of unlimited proliferation without losing pluripotency. Scognamiglio et al. now reveal that Myc depletion shifts mESCs into a dormant state reminiscent of embryonic diapause in which pluripotency remains fully preserved, thus decoupling pluripotency from proliferative programs.
Topics: Animals; Embryonic Stem Cells; Female; Genes, myc; Male; Proto-Oncogene Proteins c-myc
PubMed: 26871623
DOI: 10.1016/j.cell.2016.01.050 -
Frontiers in Bioscience (Scholar... Jan 2012The FES gene was first discovered as a protein-tyrosine kinase-encoding retroviral oncogene. The ability of v-FES to transform cells in vitro and initiate cancer in vivo... (Review)
Review
The FES gene was first discovered as a protein-tyrosine kinase-encoding retroviral oncogene. The ability of v-FES to transform cells in vitro and initiate cancer in vivo has been established by cell culture, engraftment and transgenic mouse studies. The corresponding cellular c-FES proto-oncogene encodes a cytoplasmic FES protein-tyrosine kinase with restrained catalytic activity relative to its retrovirally encoded homologs. These observations have stimulated a search for mutations or inappropriate expression of c-FES in human cancers and research aimed at understanding the functions of the FES kinase and its potential involvement in cancer and other diseases. Paradoxically, although first identified as an oncogene, genetic evidence has also implicated c-fes as a potential tumor suppressor. This review will describe observations from basic and translational research which shapes our current understanding of the physiological, cellular and molecular functions of the FES protein-tyrosine kinase and its potential roles in tumorigenesis. We also propose a model to reconcile the conflicting oncogenic and tumor suppressor roles of c-FES in tumorigenesis.
Topics: Animals; Cell Transformation, Neoplastic; Genes, Tumor Suppressor; Humans; Mice; Mice, Transgenic; Mutation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fes; Proto-Oncogenes
PubMed: 22202072
DOI: 10.2741/280