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At least 19 recordsLinked to original sources

PubMed1989

Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors.

The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, we have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10(4) foci per microgram of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, we found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which we had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo (M. Souyri, C. F. Koehne, P. V. O'Donnel, T. H. Aldrich, M. E. Furth, and E. Fleissner, Virology 158:69-78). However, similarly poor oncogenicity was also observed when the v-H-ras coding sequence was inserted in pSV(X) vector, which indicated that the vector sequences play a crucial role in the pathogenicity of a given oncogene. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

Animals↗

PubMed1992

Cooperation between the H-ras oncogene and a truncated derivative of the v-myb oncogene in transformation of hamster embryo fibroblasts.

The ras oncogenes alone fully transform established (immortalized) rodent fibroblasts in a few days, but generally transform early-passage fibroblasts only partially, unless their action is complemented by that of a nuclear, immortalizing, oncogene. Here we show that transfection of second-passage Syrian hamster embryo fibroblasts (HEFs) by the EJ-H-ras oncogene coupled to the neo gene, followed by selection with G418, gives rise to apparently normal, or only slightly transformed, clonal colonies, only a few of which become established. The study of two established clonal lines showed that they acquired only after some weeks, and stepwise, the main characteristics of full neoplastic transformation, i.e. anchorage independence, reduced requirement for serum growth factors and tumorigenicity. Later both clonal lines became increasingly tumorigenic and completely independent of exogenous growth and attachment factors, without increase in the expression of the H-ras oncogene. Transfection of one of the clones, early after its isolation, with a truncated derivative of the nuclear v-myb oncogene devoid of its transcriptional negative regulatory domain and able to partially transform chicken embryo fibroblasts [(myb(KXANM)] gave rise to more transformed cells, expressing both EJ-H-ras and myb(KXANM), which became tumorigenic earlier than the controls and remained more tumorigenic later on. With more efficient transfection techniques, numerous foci of fully transformed cells were subsequently obtained, in a few days, in cultures transfected sequentially with EJ-H-ras(neo) and myb(KXANM) and in cultures co-transfected with the two oncogenes. Highly tumorigenic, serum-independent and immortalized clones expressing both oncogenes were obtained from these cultures. Hence, the truncated myb(KXANM) oncogene accelerate the stepwise transformation of unestablished HEFs by the EJ-HH-ras oncogene and, together with this oncogene, fully transforms these same cells in a single step. The two oncogenes acting in cooperation also induce cell immortalization, but myb(KXANM), by itself, is not an immortalizing oncogene. No cooperation was observed between EJ-H-ras(neo) and the unaltered v-myb oncogene.

Animals↗

PubMed1989

[Detection of cellular proto-oncogenes and oncogenes].

Detection of proto-oncogenes in normal cells and oncogenes in cells of solid tumors and in leukemic cells confirmed the assumption on the genetic basis of neoplastic cell transformation. Proto-oncogenes constitute a specific group of genes involved in physiological processes of the cell. Inappropriately expressed forms of proto-oncogenes are referred to as oncogenes. Proto-oncogenes and oncogenes were detected either by means of animal oncogenic viruses, in in vitro transfection experiments, or by means of some cytological methods revealing chromosomal abnormalities. Proto-oncogenes were detected in cells of phylogenetically very distant species, suggesting their importance in the regulation of the cell cycle.

Animals↗

PubMed1992

The v-ski oncogene cooperates with the v-sea oncogene in erythroid transformation by blocking erythroid differentiation.

The avian retrovirus oncogene v-ski was analysed for its ability to alter the differentiation program of erythroid cells and to cooperate with tyrosine kinase oncogenes in leukemogenesis. For this, a retrovirus combining v-ski with a temperature-sensitive version of the v-sea oncogene was constructed. In transformed erythroblasts, v-ski disturbed the concerted expression of several erythrocyte genes, leading to an abnormal erythroblast phenotype. Expression levels of hemoglobin and erythrocyte anion transporter (band 3) were elevated, while expression of the erythroid-specific histone H5 was strongly suppressed. v-ski could also be shown to repress or severely retard the temperature-induced erythroid differentiation of v-ski/ts-v-sea-transformed cells. The undifferentiated cells had an abnormal erythroblast or early reticulocyte phenotype characterized by unusually low levels of histone H5. In chicks, the v-ski/ts-v-sea virus displayed enhanced leukemogenicity compared with viruses containing just the single oncogenes. Thus, v-ski cooperates with tyrosine kinase oncogenes in a similar fashion to the v-erbA oncogene, however the pattern of genes affected by these two oncogenes is different.

Animals↗

PubMed1988

Differential expression of preproenkephalin and transin mRNAs following oncogenic transformation: evidence for two classes of oncogene induced genes.

FR3T3 rat embryo fibroblast cells express preproenkephalin mRNA after transformation by polyoma virus middle T or Ha-ras oncogenes. This effect was not seen in another rat embryo fibroblast cell line (Rat-1) or in FR3T3 cells transformed by Rous sarcoma virus, bovine papilloma virus type I or SV40. The elevation in preproenkephalin mRNA levels is thus cell specific and oncogene specific. These results contrast with those obtained for transin mRNA, which was observed in both Rat-1 and FR3T3 cells transformed by a number of different oncogenes. The expression of transin RNA correlated with the expression of the transformed phenotype. We suggest that genes induced by oncogenes in a given cell will fall into two classes: those linked to the expression of the transformed phenotype (expression induced by all oncogenes conferring this phenotype) and those induced as a consequence of activation of a specific cellular signaling system (expression induced by a subset of oncogenes linked to the signaling system in question). This system may prove useful in distinguishing oncogene-induced events that are related to cellular transformation from those that are secondary to eliciting the transformed phenotype.

Animals↗

PubMed1990

Oncogenes and anti-oncogenes in tumorigenesis.

Recent advances have led to the identification of cellular genes which are involved in the initiation and progression of tumorigenesis. The proto-oncogenes, which normally participate in the regulation of cell proliferation and differentiation, can become oncogenes through alterations in the regulation of their expression and/or their coding sequences. Their contribution to the tumorigenic phenotype is dominant. The anti-oncogenes or tumor suppressor genes or recessive oncogenes are normally implicated in a negative regulation of cellular proliferation. The loss of their activity contributes to tumorigenesis in a recessive manner. Genetic events activating proto-oncogenes or inactivating anti-oncogenes accumulate in the same cell during tumor progression and co-operate to determine the malignant invasive phenotype of advanced tumors.

Cell Differentiation↗

PubMed1988

[Oncogenes and oncogene products in urogenital cancer cells].

Recent development in microbiology and genetic engineering has provided the identification and characterization of so-called 'oncogenes'. The concept of oncogenes has much stimulated intense interest in searching the cause of uncontrolled cell growth and factors responsible for formation of tumors. Because of the fact that oncogenes were first discovered in an established cell line derived from patient with bladder tumor, the association between oncogenes and genitourinary cancer has much attention. Variety of pathways of tumor development in bladder cancer can be divided in two major forms, low grade papillary tumor and high grade infiltrating tumor. Activation and a sequence of oncogenes may be relevant to the ultimate expression of these separate pathways. Concept of initiation and promotion may also be factored into these consideration. The application of these principles to the different pathways of tumor development such as in bladder, kidney and prostate cancers, supports the concept that oncogenes may be required to production of malignant tumors. The purpose of this paper is to review recent evidence that has enhanced our understanding of the genetic basis of cancer development in the genitourinary tract cancer.

Aged↗

PubMed1989

Nakahara memorial lecture. Hereditary cancer, oncogenes, and anti-oncogenes.

Dominantly heritable predisposition to cancer is well known, even if rare. Such heritable cases are known for most cancers. Predisposition is usually to one or a few specific cancers, and the kinds of pedigrees that are found suggest the existence of an array of 50 or so such cancer genes. Penetrance is usually high, as is the relative risk for a particular tumor. The inherited event is insufficient to cause cancer; at least one other (somatic) event must occur. For one tumor, retinoblastoma, the total number of necessary events seems to be two for both the hereditary and non-hereditary forms, and those events involve mutation or loss of the two copies of a tumor suppressor gene on chromosome 13. Analyses of tumors with polymorphic syntenic DNA probes and for abnormality of the gene itself have provided a picture of the kinds of first and second events that can occur. Several other tumors may follow the retinoblastoma scenario, including tumors associated with multiple endocrine neoplasia type 1 and with neurofibromatosis type 2, and identify the loci of several other putative anti-oncogenes. Still other hereditary cancer genes have been mapped, but evidence that they are suppressor genes is incomplete. It is possible that the inherited mutation may sometimes occur in an oncogene, although no such cases have been validated. In most, perhaps all, tumors, further genetic changes occur. In some instances these appear to be in oncogenes, and sometimes in anti-oncogenes. Some of these events appear to play a role similar to that of promotion in experimental carcinogenesis, whereas others are clearly important in progression. The process is particularly complicated in some of the common carcinomas, where changes in both oncogenes and anti-oncogenes are common.

Carcinoma, Renal Cell↗

PubMed1991

Abnormal structure of the canine oncogene, related to the human c-yes-1 oncogene, in canine mammary tumor tissue.

Cellular oncogenes of genomic DNA in 6 canine primary mammary tumors were screened by Southern blot analysis, using 7 oncogene probes. A canine genomic oncogene related to the human c-yes-1 oncogene was detected as abnormal bands in solid carcinoma genomic DNA digested with EcoRI, HindIII, HindIII-EcoRI, or HindIII-BamHI. Comparison was made between other tumor specimens and control specimens obtained from 4 clinically normal dogs--1 mixed breed and 3 Shiba Inu dogs (the same breed as the dog from which the solid carcinoma was obtained). These abnormal bands were 0.1 to 1 kilobase shorter than the normal gene. However, digestion of genomic DNA obtained from normal WBC of this dog also produced all of the abnormal bands as observed in digested DNA from the solid carcinoma tissue. Therefore, in this dog, the genomic DNA of all somatic cells from the ontogenic stage still had the abnormal sequences related to the human c-yes-1 oncogene, and it is possible that this abnormal structure may have some role (eg, as an initiator) in tumorigenesis or the progression of this tumor.

Animals↗

PubMed1988

Complementary DNA clones of chicken proto-oncogene c-ets: sequence divergence from the viral oncogene v-ets.

The avian acute leukemia virus E26 induces erythroblastosis and myeloblastosis in chickens. The oncogene of this virus includes sequences derived from the cellular gene designated c-ets, which is normally expressed in lymphoid cells and whose product is a protein of apparent molecular weight ca. 54,000 daltons. Complementary DNA clones representing the major transcript of the chicken c-ets proto-oncogene were isolated from a spleen cell library. Sequence analysis of the cDNA revealed that it contains an open reading frame encoding a polypeptide of 441 amino acids with a molecular weight of 49,932 daltons. This open reading frame can be transcribed and translated in vitro into a 50 kd protein that is specifically immunoprecipitated with antiserum to the v-ets oncogene product. Within the central region of homology between c-ets and v-ets, there are only 5 nucleotide substitutions resulting in 4 amino acid changes. However, coding sequences at the 5' and 3' ends of the v-ets oncogene and the chicken c-ets cDNA differ from one another. These changes may be responsible for the differential functions of c-ets and v-ets in cells of different hematopoietic lineages and may account for the pathogenic properties of the v-ets oncogene.

Amino Acid Sequence↗

PubMed1988

Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene.

Established REF52 cells (rat embryo fibroblasts) completely resist stable transformation by ras oncogenes, and simian virus 40 large tumor (T) antigen collaborates with ras to convert REF52 cells to tumorigenic state. A temperature-sensitive simian virus 40 large T antigen (encoded by tsA58) allowed the T24 Ha-ras oncogene to transform REF52 cells in a temperature-dependent manner. Two thirds of the clones transformed with tsA58 and ras became arrested in G2 or late S phase when shifted to a nonpermissive temperature for T antigen stability. Thus, ras induced growth arrest rather than stable transformation in the absence of a functional collaborating oncogene. These results indicate that collaborating oncogenes can regulate cellular responses to ras and have implications regarding therapeutic strategies to control tumor cells expressing activated ras oncogenes.

Animals↗

PubMed1992

Identification of the product of two oncogenic rearranged forms of the RET proto-oncogene in papillary thyroid carcinomas.

In papillary thyroid carcinomas, we have identified two tumor-specific rearrangements of the RET proto-oncogene leading to the formation of different transforming fusion products sharing the tyrosine kinase (tk) domain of the proto-oncogene and designated ptc-1 and ptc-2. We have analysed ptc-1 and ptc-2 products by immunoprecipitation with specific anti-RET antibodies followed by immunoblotting with the same reagent or with antibodies specific for phosphotyrosine (P-tyr) residues. The anti-RET antibodies were reactive with 64-kDa (p64ptc-1) and 81-kDa (p81ptc-2) proteins from lysates of ptc-1 and ptc-2 transformed cells, respectively, and identified two proteins of 140 kDa and 160 kDa from extracts of SK-N-SH, a neuroblastoma cell line previously shown to express two differently glycosylated forms of the normal RET product. The anti P-tyr antibodies, while detecting the same p64ptc-1 and p81ptc-2 proteins from ptc-1 and ptc-2 extracts, did not show any specific band in the neuroblastoma lysates. An additional set of experiments led us to conclude that, whereas the normal product of the RET proto-oncogene is a membrane-associated receptor-like molecule not intrinsically phosphorylated on tyrosine, both oncogenic forms of RET, ptc-1 and ptc-2, are constitutively phosphorylated on tyrosine, display an 'in vitro' autophosphorylation activity, are translocated from the membrane to the cytoplasm and are apparently unaffected by protein kinase C modulation.

3T3 Cells↗

PubMed1992

Activation of oncogenes and/or inactivation of anti-oncogenes by reactive oxygen species.

Abundant evidence indicates that reactive oxygen species (ROS) are involved in mutagenesis and carcinogenesis. These chemical-generated or phagocyte-released ROS are known to cause a variety of genetic alterations which lie at the heart of the carcinogenic process. ROS have also been shown to cause malignant transformation of normal cells, and to increase expression of certain proto-oncogenes such as c-fos and c-jun. It is known that certain proto-oncogenes and anti-oncogenes may serve as the targets of carcinogens of various sorts. I hypothesize that ROS-mediated DNA damage may cause mutations and/or deletions in certain specific coding regions of tumor-related genes, and could be responsible for subsequent activation of oncogenes and/or inactivation of anti-oncogenes.

Animals↗

PubMed1992

Oncogenes, anti-oncogenes and the immune response to cancer: a mathematical model.

We develop a mathematical model for the initial growth of a tumour after a mutation in which either an oncogene is expressed or an anti-oncogene (i.e. tumour suppressor gene) is lost. Our model incorporates mitotic control by several biochemicals, with quite different regulatory characteristics, and we consider mutations affecting the cellular response to these control mechanisms. Our mathematical representation of these mutations reflects the current understanding of the roles of oncogenes and anti-oncogenes in controlling cell proliferation. Numerical solutions of our model, for biologically relevant parameter values, show that the different types of mutations have quite different effects. Mutations affecting the cell response to chemical regulators, or resulting in autonomy from such regulators, cause an advancing wave of tumour cells and a receding wave of normal cells. By contrast, mutations affecting the production of a mitotic regulator cause a slow localized increase in the numbers of both normal and mutant cells. We extend our model to investigate the possible effects of an immune response to cancer by including a first order removal of mutant cells. When this removal rate exceeds a critical value, the immune system can suppress tumour growth; we derive an expression for this critical value as a function of the parameters characterizing the mutation. Our results suggest that the effectiveness of the immune response after an oncogenic mutation depends crucially on the way in which the mutation affects the biochemical control of cell division.

Animals↗

PubMedDate not supplied

Viral oncogenes, proto-oncogenes and homoeotic genes related to cell proliferation and differentiation.

Molecular studies on viral oncogenes and their products have led to the discovery of physiological proto-oncogenes, involved in the control of cell proliferation and gene activation. Other genetic and molecular investigations, initiated in Drosophila melanogaster and continued in different multicellular eukaryotes, have made evident the homoeotic genes, which are directly correlated with cell specialization, in the complex processes of differentiation and morphogenesis. Both gene classes are conserved to a high extent during evolution. They are involved in the eukaryotic mechanisms of differentiation control and proto-oncogenes, in particular, are related to malignant transformation. Some available data suggest a certain extent of relatedness between the gene products of both gene classes. A differentiation trigger model, including retroviral transposition, homoeotic genes and proto-oncogenes is discussed.

Animals↗

PubMed1990

Strategies for the analysis of oncogene overexpression. Studies of the neu oncogene in breast carcinoma.

The development of a consistent strategy for the analysis of oncogene expression at the cellular level is essential for understanding the roles of these genes in the development and progression of human neoplasia. Detection of the neu oncogene products in breast carcinoma was selected as a model for analysis of oncogene expression. Fifty-two primary human breast carcinomas were evaluated by quantitation of neu DNA amplification and mRNA expression and by localization of neu mRNA and protein (p 185) at the cellular level by in situ hybridization (ISH) and immunohistochemistry (IHC). The specificity and sensitivity of the molecular and immunologic probes for neu were established with the use of genetically engineered cell lines that overexpressed either neu or epidermal growth factor receptor (EGFR). Twenty-nine percent of breast carcinomas demonstrated neu DNA amplification and mRNA overexpression, and there was close correlation between the level of neu mRNA expression and detection of neu gene products by ISH and IHC. Thirty-two percent of carcinomas demonstrated neu mRNA overexpression by ISH. The immunohistochemical method using TA1 monoclonal antibody for p185 was exquisitely sensitive in acetone-fixed frozen sections and provided an excellent approach for judging overexpression as confirmed by the various molecular analyses. All areas of nonmalignant breast epithelium stained weakly, and a wide range of staining intensity was observed in malignant breast epithelium, with 31% of carcinomas judged to be p185 overexpressors. Heterogeneous expression of p185 was seen in some carcinomas. This study provides a strategic approach for the evaluation of oncogene expression in human tumors.

Antibodies, Monoclonal↗

PubMed1985

Promoter region of the human Harvey ras proto-oncogene: similarity to the EGF receptor proto-oncogene promoter.

Regulation of transcription of members of the ras gene family undoubtably plays an important role in controlling cellular growth. Examination of this level of regulation requires identification of the promoter regions of the ras proto-oncogenes. Four major transcriptional start sites were detected in the human Harvey ras 1 proto-oncogene. The promoter region contains neither a TATA box nor a CAAT box in their characteristic upstream positions, has an extremely high G+C content (80 percent), and contains multiple GC boxes including seven CCGCCC repeats and three repeats of the inverted complement, GGGCGG. This region has strong promoter activity when placed upstream from the chloramphenicol acetyl transferase gene and transfected into monkey CV1 cells. In these ways the Harvey ras 1 proto-oncogene promoter resembles the promoter of the gene encoding the epidermal growth factor (EGF) receptor. The similarity between the two proto-oncogene promoters may be relevant to the mechanism by which the expression of such "growth control" genes is regulated.

DNA Restriction Enzymes↗

PubMed1987

Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene.

We investigated alterations in the structure and expression of oncogenes in mammary tumors and mammary tumor-derived cell lines. In 16 of 95 samples, we detected amplification of the human neu oncogene, also known as c-erB-2, accompanied by overexpression in the tumors from which intact RNA could be isolated. In 10 of these DNAs, the linked oncogene c-erbA was also amplified, whereas another gene on human chromosome 17, p53, was present in normal copy numbers. Overexpression of c-erbA could not be detected in the tumors analyzed. The relatively high frequency of neu amplification points to a functional role in human breast cancer. Coamplification of the c-erbA oncogene could contribute to this disease as well but is most likely fortuitous.

Age Factors↗