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PubMed1980

Nucleotide sequence of an avian sarcoma virus oncogene (src) and proposed amino acid sequence for gene product.

The transforming gene (src) of avian sarcoma virus (ASV) and adjacent regions of the viral genome have been isolated by molelcular cloning of viral DNA. Their nucleotide sequence encompasses the whole of src and the portion of the gene env that encodes gp 37, one of two glycoproteins found in the viral envelope. Src encodes a single, hydrophobic protein with structural features that conform to previous descriptions descriptions of the gene product (pp60src). It appears that a single viral protein is responsible for both the initiation and maintenance of neoplastic transformation by avian sarcoma virus. Neither src nor its product bear any obvious structural relationship to several other viral oncogenes and their encoded proteins. Src is flanked by a repeated nucleotide sequence that may facilitate frequent deletion of the gene from the viral genome.

Alpharetrovirus↗
PubMed1985

Low level of cellular protein phosphorylation by nontransforming overproduced p60c-src.

We have previously found that Rous sarcoma virus variants in which the viral src (v-src) gene is replaced by the cellular src (c-src) gene have no transforming activity. In this study, we analyzed the basis for the inability of the p60c-src overproduced by these variants to transform cells. Phosphorylations of tyrosine residues in total cell protein or in cellular 34K protein are known to be markedly enhanced upon infection with wild-type Rous sarcoma virus. We found that these tyrosine phosphorylations were only slightly increased in the c-src-containing virus-infected cells, whereas both levels were significantly increased by infection with wild-type Rous sarcoma virus, or transforming mutant viruses which are derived from c-src-containing viruses by spontaneous mutation. Phosphorylation at tyrosine 416 of p60 itself was also extremely low in overproduced p60c-src and high in p60s of transforming mutant viruses. In immunoprecipitates with monoclonal antibody, the overproduced p60c-src had much lower casein tyrosine kinase activity than did p60v-src. We previously showed that p60 myristylation and plasma membrane localization may be required for cell transformation. p60c-src was similar to transforming p60s in these properties. These results strongly suggest that the low level of tyrosine phosphorylation by overproduced p60c-src accounts for its inability to transform cells.

Animals↗
PubMed1987

Identification of an amino terminal domain required for the transforming activity of the Rous sarcoma virus src protein.

Transformation of chicken cells by Rous sarcoma virus (RSV) requires the functional expression of the viral src protein, a tyrosine protein kinase, pp60src. Variants of RSV containing deletions within the amino terminal one-third of the src protein have been identified that exhibit either temperature-sensitive or transformation-defective phenotype when used to infect chicken embryo cells. To define the regions within the amino terminal portion of pp60src that influence morphological transformation, a series of overlapping deletion mutations in the src gene of Prague A RSV (Pr A RSV) were constructed and their biological and biochemical properties were analyzed. Deletions within the src gene which remove amino acid residues 38 to 142 had minimal effects on the ability of the mutant viruses to induce cellular transformation. However, deletions, which impinged upon the region of the src gene encoding residues 142 to 169, inhibited cellular transformation. A variant containing a deletion of amino acid residues 169 to 225, was temperature sensitive for transformation. Structurally altered src proteins recovered from cells infected with transformation-defective variants exhibited a somewhat reduced tyrosine protein kinase activities when assayed in the immune complex kinase assay. Analysis of the in vivo phosphorylation of a pp60src substrate, the 36-kDa protein, revealed virtually wild-type levels of phosphorylation in cells infected with the transformation-defective mutants. These studies suggest that the region of the Pr A RSV src protein delineated by amino acid residues 142 to 169 is essential for initiation and maintenance of morphological transformation of chicken cells in culture.

Amino Acid Sequence↗
PubMed1987

Rous sarcoma virus mutant dlPA105 induces different transformed phenotypes in quail embryonic fibroblasts and neuroretina cells.

dlPA105 is a spontaneous variant of Rous sarcoma virus, subgroup E, which carries a deletion in the N-terminal portion of the v-src gene coding sequence. This virus was isolated on the basis of its ability to induce proliferation of quiescent quail neuroretina cells. The altered v-src gene encodes a phosphoprotein of 45,000 daltons which possesses tyrosine kinase activity. DNA sequencing of the mutant v-src gene has shown that deletion extends from amino acid 33 to 126 of wild-type p60v-src. We investigated the tumorigenic and transforming properties of this mutant virus. dlPA105 induced fibrosarcomas in quails with an incidence identical to that induced by wild-type virus. Quail neuroretina cells infected with the mutant virus were morphologically transformed and formed colonies in soft agar. In contrast, dlPA105 induced only limited morphological alterations in quail fibroblasts and was defective in promoting anchorage-independent growth of these cells. Synthesis and tyrosine kinase activity of the mutant p45v-src were similar in both cell types. These data indicate that the portion of the v-src protein deleted in p45v-src is dispensable for the mitogenic and tumorigenic properties of wild-type p60v-src, whereas it is required for in vitro transformation of fibroblasts. The ability of dlPA105 to induce different transformation phenotypes in quail fibroblasts and quail neuroretina cells is a property unique to this Rous sarcoma virus mutant and provides evidence for the existence of cell-type-specific response to v-src proteins.

Animals↗
PubMed2000

Natural selection and early changes of phenotype of tumor cells in vivo: acquisition of new defense mechanisms.

This review summarizes results obtained in the author's and collaborating laboratories within the last decade and is designed to attract the attention of researchers to discrete biochemical mechanisms of protection acquired in vivo by cells of malignant tumors against effectors of innate antitumor immunity. Tumor progression in vivo is associated with the appearance and selection of tumor cells with new specific characteristics: a high level of H(2)O(2)-catabolizing (antioxidant) activity (H(2)O(2)CA) and the ability for immediate release of E2-type prostaglandin (PGES) on contact with natural killers, macrophages, and neutrophils; the expression of the [H(2)O(2)CA + PGES] phenotype provides the tumor cells with two mechanisms of local protection against effectors of innate and acquired antitumor immunity. This results in a 10-100-fold less effective rejection of tumor cells in immune and normal animals and corresponding increase of tumorigenicity. The in vitro transformation of normal fibroblasts, spontaneous or induced by oncogenes LTSV40, E1a,b, Ha-ras, myc, and also by p53(175) and bcl-2 does not result in the [H(2)O(2)CA + PGES] phenotype expression, but during subsequent in vivo growth of the above-mentioned transformants the selection of tumor cells of the [H(2)O(2)CA + PGES] phenotype is correlated with a 30-200-fold increase in their tumorigenicity (accompanied or not accompanied by spontaneous metastatic activity). Unlike the transformation induced by the above-mentioned oncogenes, the transformation of normal cells by the v-src gene results in the [H(2)O(2)CA + PGES] phenotype expression. The data presented confirm the determining role of the v-src gene in the expression of the [H(2)O(2)CA + PGES] phenotype. In various primary viral carcinogenesis (SV40, SA7(C8)) the natural selection of cells expressing the [H(2)O(2)CA + PGES] phenotype begins even within the latent period and can be completed by the appearance of primary tumors.

Animals↗
PubMed1986

Control of expression of an integrated Rous sarcoma provirus in rat cells: role of 5' genomic duplications reveals unexpected patterns of gene transcription and its regulation.

Rat cells transformed by Rous sarcoma virus frequently contain duplications of viral (and sometimes cellular) DNA 5' to the integrated provirus, suggesting that such rearrangements favor provirus expression. In one cell line, A11, the duplication includes the viral src gene and proviral sequences that flank it. We examined three possible roles for this structure. Since the proviral v-src gene transformed recipient cells upon DNA transfer and was the major template for v-src transcription in A11 cells, the presence of v-src in the duplication is presumably not necessary for transformation. Since the size and structure of transcripts from the proviral v-src gene in A11 cells were conventional, the duplication does not facilitate transformation by providing a novel transcriptional strategy. Thus, we favor the concept that the duplication either attenuates a negative effect of flanking elements at the host chromosome integration site or augments the positive regulation of conventional provirus expression or both. Gene transfer and transcription analyses with both genomic and cloned DNA showed that the mechanisms of such regulatory phenomena are complex. Identical sequences in the provirus and the 5' duplication displayed different patterns of expression in A11 cells that could be disrupted in segments of cloned DNA. Among the elements that influenced such expression were sequences from the gag-pol region of the provirus.

Animals↗
PubMed1982

Restriction endonuclease and nucleotide sequence analyses of molecularly cloned unintegrated avian tumor virus DNA: structure of large terminal repeats in circle junctions.

Avian tumor virus supercoiled DNA was isolated from infected quail tumor cells and molecularly cloned in pBR322. Four different recombinant clones denoted pATV-6, pATV-7, pATV-8, and pATV-9 were characterized in detail by restriction endonuclease mapping and by DNA sequencing. The results of these studies indicate that (i) the two large terminal repeats (LTRs) present in PATV-6, are different sizes, (ii) pATV-8 and pATV-9 contain only one LTR, (iii) pATV-7 contains an inversion of 0.6 kilobase in the env gene and a deletion of the U3 region and the src gene, and (iv) the src gene is deleted in pATV-6 and pATV-9. Circle formation from linear molecules was also examined in several of the clones by DNA sequencing through the circle joint. pATV-6 is an example of one class of circular molecules and contains a partially repeated LTR similar to that reported by Ju and Skalka (Cell 22:379-386, 1980). A second class of circles was exemplified by pATV-8 and pATV-9, which contain a single copy of the LTR with no base changes or deletions. This is in contrast to a class of circles containing a complete double LTR structure described by Swanstrom et al. (Proc. Natl. Acad. Sci. U.S.A. 78:124-128, 1981) and suggests that circles containing a single intact LTR may be formed by a homologous recombinational event in which an entire LTR or complementary regions from both LTRs are removed from the linear DNA molecule during circularization.

Avian Sarcoma Viruses↗
PubMed2000

Phylogenetic utility of the tyrosine kinase gene X-src for assessing relationships among representative cichlid fishes.

The nuclear gene X-src is a member of the tyrosine-kinase class of proto-oncogenes whose normal product is localized within the cytoplasm of the cell. The X-src gene has been used in only a few phylogenetic studies, each focusing on systematics of killifishes (Cyprinodontiformes). The present study is an attempt to examine the phylogenetic utility of X-src for uncovering relationships of representative cichlid fishes, especially the cichlids of Middle America. The family Cichlidae is a species-rich group of tropical freshwater fish made up of more than 1000 species which show a Gondwanan pattern of distribution. Cichlid fish have been the focus of numerous studies ranging from behavioral to biogeographical to systematic in nature. Particular emphasis has focused on the cichlids of the African Great Lakes and the explosive adaptive radiation of this group. However, Neotropical cichlids have received considerably less attention than their African counterparts. Our findings regarding the utility of X-src concur with those of previous phylogenetic analyses showing the exons of X-src to be highly conserved and useful mostly for revealing deep relationships among taxa. Like previous X-src studies, we also found the intron sequences of the gene to be variable in length and difficult to align across distantly related taxa but they provided useful information for resolving relationships among more closely related taxa. The X-src phylogeny supports the monophyly of Neotropical cichlids and cichlasomines groups A (=heroines) + B (=cichlasomines). A highly resolved tree is obtained within the heroines but little support is evident for most nodes based on the low number of unambiguous substitutions. The X-src gene is likely to be quite useful for resolving deep phylogenetic relationships such as those among major groups of actinopterygian fishes.

Animals↗
PubMed1994

Structure and expression of Spk-1, an src-related gene product found in the planarian Dugesia (G) tigrina.

A cDNA clone encoding a 497 amino acid protein 75% similar to most Src proteins has been isolated from the planarian Dugesia (Girardia) tigrina (Platyhelminthes; Turbellaria) by PCR followed by screening procedures. This gene product has been designated Spk-1 as it is the first Src-related kinase isolated in a planarian. The predicted amino acid sequence of Spk-1 suggest that it is anchored to the plasma membrane and that it interacts with other phosphotyrosine proteins. Spk-1 is expressed in both intact and regenerating organisms as an mRNA transcript of about 1.9 kb. Planarians, which conserve most features of the common ancestor to protostomian and deuterostomian phyla, are the most primitive triploblastic organisms from which a protein tyrosine kinase gene product has been isolated. The presence of this gene product in such a primitive organism, and its presumed role, are discussed.

Amino Acid Sequence↗
PubMed1994

Function-dependent cooperation between oncogene activation and nonrandom chromosome change during tumorigenic conversion of Syrian hamster cells.

We determined the tumorigenicity of SHOK cells, a Syrian hamster cell line, morphologically transformed by the introduction of either c-Ha-ras, c-Ki-ras, N-ras, v-mos, v-fgr, or v-src genes. When 1 x 10(6) cells were injected subcutaneously into nude mice, SHOK cells containing one of those oncogenes gave rise to tumors within 3 weeks, while the parental SHOK cells, or SHOK cells containing the neo gene, did not show tumorigenicity even 200 days after injection. From karyotype analysis, the addition of chromosome 3 was consistently found in tumor cells derived from SHOK cells containing the c-Ha-ras, c-Ki-ras, or v-mos genes, and the acquisition of chromosome 9 was a common change observed in tumor cells derived from SHOK cells morphologically transformed by the v-fgr or v-src gene. No consistent chromosomal change was observed in tumor cells containing the N-ras gene. The results obtained from Southern blot analysis showed that amplification of introduced oncogenes was detected in the case of c-Ha-ras, c-Ki-ras, N-ras, v-fgr, and v-src genes. These results indicate that nonrandom chromosome changes, along with the amplification of introduced oncogenes, are required for the tumorigenic conversion. Our findings propose the possibility that secondary chromosomal changes associated with the tumorigenic conversion of morphologically transformed cells occur dependent on the function of the primary activated oncogene introduced.

Animals↗
PubMed1984

Current knowledge of mechanisms of viral carcinogenesis.

Retroviruses are RNA-containing viruses using reverse transcriptase to produce DNA copies capable of insertion into host chromosomes. Appropriate genes are required to confer transforming ability to retroviruses. The src gene, a 60,000-dalton protein with protein kinase activity, is required by avian viruses to induce sarcomas. Normal cells have a gene (sarc) similar to the src gene. Retroviruses with oncogenic properties can arise by recombining with genes on the host chromosome. Herpesviruses, adenoviruses, and papovaviruses have transforming properties residing in only a portion of the genome. Probably, only one to two genes are required for transformation, regardless of the complexity of the virus.

Animals↗
PubMed2000

No evidence of correlation between mutation at codon 531 of src and the risk of colon cancer in Chinese.

The protein tyrosine kinase activity of c-src proto-oncogene product, pp60(c-src), is elevated in a number of human cancers, including colon cancer. Phosphorylation of human pp60(c-src) carboxy-terminal tyrosine 530 suppresses its kinase activity. A recent report suggested that the risk of colon cancer is higher for those who carry a C-->T transition mutation on codon 531 (Gln-531-->Amber-531) of src gene. This mutation caused a prematured translation termination and up-regulated the kinase activity. To examine whether this mutation could be a risk factor for colon carcinoma in the Chinese population, we used the same PCR-based assay to analyze src genotypes of 131 colon cancers and other various types of carcinoma. No mutation was detected in all specimens that were screened in this study. Thus, mutation at Gln-531 of src gene does not seem to be involved in the development of colon cancer in Chinese ethnicity.

China↗
PubMed1991

Neurite extension and protein tyrosine phosphorylation elicited by inducible expression of the v-src oncogene in a PC12 cell line.

Tyrosine-specific protein kinase activity in neuronal differentiation was studied in a PC12 pheochromocytoma cell line (PC12-B9) produced by stable transfection with an inducible v-src gene encoding an activated tyrosine kinase (pp60v-src) under the transcriptional control of the mouse metallothionine I gene promoter. Induction of pp60v-src expression with Cd2+ and Zn2+ resulted in the reversible differentiation of PC12-B9 cells into neuron-like cells. pp60v-src elicited morphological differentiation with apparent first order kinetics at the same rate as NGF-directed neurite outgrowth in PC12-B9 cells. v-src gene expression enhanced the rate of NGF-directed neurite extension in an additive manner. Induction of pp60v-src alone constitutively increased the levels of phosphotyrosine-modified proteins (130-120, 90, 83, 65, 60/59, 36 kDa) detected by immunoblotting with phosphotyrosine antibodies. NGF treatment of PC12-B9 cells transiently increased the levels of distinct phosphotyrosine-modified proteins (108, 46, 42 kDa), as well as common substrates, including a 59-kDa protein that comigrated with alpha-tubulin. Phosphotyrosine-modified proteins were not synergistically increased in PC12-B9 cells induced for both v-src and NGF. The nonsynergistic effects of v-src gene expression on neurite outgrowth and phosphorylation suggest that pp60v-src induces PC12 cell differentiation by an intracellular signaling pathway that is largely distinct from that induced by NGF.

Adrenal Gland Neoplasms↗
PubMed1998

The human c-Src proto-oncogene promoter contains multiple targets for triplex-forming oligonucleotides.

The overexpression and activation of the human c-Src proto-oncogene is closely associated with cancer of the colon and breast. Characterization of the 5' region of the c-Src gene revealed that the promoter is very GC rich, regulated by the Sp family of transcription factors, and contains four perfect homopolypurine/homopolypyrimidine tracts (Pu:Py tracts). These Pu:Py tracts (TC1, TC1.1, TC2, and TC3) are located near or overlap critical Spl binding sites required for full activation of the gene. Triplex-forming oligonucleotides (TFOs) can be targeted to such sequences with high affinity to form intermolecular triple-helical DNA and modulate transcriptional activity. We therefore designed a series of antiparallel purine-based TFOs and measured their ability to form triplexes with the c-Src promoter Pu:Py tracts using comigration, bandshift, and chemical footprint techniques. With one interesting exception, all of the TFOs were found to bind with specificity and high affinity (67 nM-28 nM) to their target sequences at physiologic pH. These results indicate that the c-Src gene can successfully form stable triplexes under physiologic conditions and is, therefore, an excellent candidate for triplex-mediated transcriptional downregulation.

Base Composition↗
PubMedDate not supplied

The human lck cDNA clone YT16 is a transforming oncogene.

The lck gene belongs to the src gene family and it is implicated in processes of lymphomagenesis. A full-:length lck-encoding cDNA clone, termed YT16 was isolated from a subtractive cDNA library, which was specific for expressed genes of the human Jurkat T-cell lymphoma. Sequence analysis of this molecular clone revealed major structural alterations compared to other tyrosine kinases classified as src-related genes. Firstly, a region within thw YT16 sequence surrounding the conserved ATP-binding site was modified by several short frameshift mutations. Secondly, the regulatory important tyrosine-505 residue was substituted by a threonine at this aligned position. The latter mutation was expected to result in a constitutional hypophosphorylated and thus permanently activated protein tyrosine kinase. These significant genetic alterations within the coding region of YT16 prompted us to investigate its biological relevance in vivo. To this end, we expressed YT16-specific sequences in NIH 3T3 fibroblasts and looked for morphological transformation of transfected cells. Here we report, that transformation of NIH 3T3 cells is obtained, provided that inhibitory untranslated sequences are removed from the YT16 cDNA clone. These results lend support to the notion, that structurally altered lck genes, in this study represented by the YT16 clone, may contribute to neoplastic processes in lymphoid cells.

3T3 Cells↗
PubMed1999

Combinatorial control of a neuron-specific exon.

The mouse c-src gene contains a short neuron-specific exon, N1. N1 exon splicing is partly controlled by an intronic splicing enhancer sequence that activates splicing of a heterologous reporter exon in both neural and nonneural cells. Here we attempt to dissect all of the regulatory elements controlling the N1 exon and examine how these multiple elements work in combination. We show that the 3' splice site sequence upstream of exon N1 represses the activation of splicing by the downstream intronic enhancer. This repression is stronger in nonneural cells and these two regulatory sequences combine to make a reporter exon highly cell-type specific. Substitution of the 3' splice site of this test exon with sites from other exons indicates that activation by the enhancer is very dependent on the nature of the upstream 3' splice site. In addition, we identify a previously uncharacterized purine-rich sequence within exon N1 that cooperates with the downstream intronic enhancer to increase exon inclusion. Finally, different regulatory elements were tested in multiple cell lines of both neuronal and nonneuronal origin. The individual splicing regulatory sequences from the src gene vary widely in their activity between different cell lines. These results demonstrate how a simple cassette exon is controlled by a variety of regulatory elements that only in combination will produce the correct tissue specificity of splicing.

Animals↗
PubMedDate not supplied

Effects of doxorubicin on pp60c-src kinase activity in polyoma virus MT antigen transformed cells.

Interaction between polyoma virus (Py) encoded middle tumor antigen (MTAg) and the cellular src gene product, pp60c-src, has been shown to be correlated with the enhancement of pp60c-src kinase activity and the transforming ability of the virus. In the present study, FR3T3 cells were transfected with plasmids encoding MTAg and used to study the effects of the antineoplastic agent, doxorubicin (DOX), on pp60c-src kinase activity. Our results showed that transfection of FR3T3 cells with MTAg results in relatively high levels of MTAg expression and enhancement of pp60c-src kinase activity several folds over that observed in the control cells. Treatment of the transformed MTF4 cells with DOX up to 5 x 10(-6) M was shown to have no effect on the in vitro phosphorylation of MTAg and pp60c-src in the drug-treated cell lysates. On the contrary, treatment of src immunocomplexes with DOX resulted in a reduction in kinase activity. The inhibition appears to be a dose-dependent competition with respect to ATP concentrations.

Animals↗
PubMed1985

Overexpressed pp60c-src can induce focus formation without complete transformation of NIH 3T3 cells.

NIH 3T3 cells were transfected with plasmids containing Moloney murine leukemia virus long terminal repeats and either chicken c-src or v-src genes. In contrast with the effects observed after transfection with plasmids containing c-src and avian retrovirus or simian virus 40 promoter-enhancers (H. Hanafusa, H. Iba, T. Takeya, and F. R. Cross, p. 1-8, in G. F. Vande Woude, A. J. Levine, W. C. Topp, and J. D. Watson, ed., Cancer Cells, vol. 2, 1984; H. Iba, T. Takeya, F. R. Cross, T. Hanafusa, and H. Hanafusa, Proc. Natl. Acad. Sci. U.S.A. 81:4424-4428, 1984; R. C. Parker, R. Swanstrom, H. E. Varmus, and J. M. Bishop, p. 19-26, in G. F. Vande Woude et al., ed., Cancer Cells, vol. 2, 1984; R. C. Parker, H. E. Varmus, and J. M. Bishop, Cell 37:131-139, 1984; D. Shalloway, P. M. Coussens, and P. Yaciuk, p. 9-17, in G. F. Vande Woude et al., ed., Cancer Cells, vol. 2, 1984; D. Shalloway, P. M. Coussens, and P. Yaciuk, Proc. Natl. Acad. Sci. U.S.A. 81:7071-7075; and K. C. Wilhelmsen, W. G. Tarpley, and H. M. Temin, p. 303-308, in G. F. Vande Woude et al., ed., Cancer Cells, vol. 2, 1984), we found that both types of Moloney murine leukemia virus long terminal repeat-src expression plasmids induced focus formation, although c-src induced only 1% as many foci as v-src. The focus-selected c-src overexpressed cells had altered morphology and limited growth in soft agarose but were not tumorigenic in vivo. Cleveland digests, comparative in vitro kinase assays, secondary transfections, and immunoprecipitations indicated that focus formation was caused by rare transfection events that resulted in very high-level pp60c-src expression rather than by mutations of the transfected c-src genes. These results suggest that pp60v-src induced transformation is not a completely spurious activity which is unrelated to the function of pp60c-src but that it represents a perturbation of already existent molecular control processes involving pp60c-src.

Animals↗