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PubMed1985

Increased pp60c-src tyrosyl kinase activity in human neuroblastomas is associated with amino-terminal tyrosine phosphorylation of the src gene product.

We have observed a 20- to 40-fold increase in pp60c-src tyrosyl kinase activity in human neuroblastoma cell lines over that found in either human glioblastoma cells or human fibroblasts. The level of c-src gene transcripts and pp60c-src protein synthesis in the neuroblastoma cells was not significantly increased when compared to the levels found in glioblastoma cells. Approximately one-half of the pp60c-src molecules synthesized during a 4-hr [35S]methionine or [32P]orthophosphate labeling period in neuroblastoma cells were found to migrate more slowly on NaDodSO4/polyacrylamide gels than pp60c-src molecules labeled in glioblastoma cells. Peptide and phosphoamino acid analysis of the in vivo phosphorylated c-src molecules from these two cell types revealed that pp60c-src molecules from the neuroblastoma cells possess in the amino-terminal portion of the protein at least one unique tyrosine phosphorylation site not found in pp60c-src derived from glioblastoma cells.

Cell Line↗

PubMed1980

Role of src gene in growth regulation of Rous sarcoma virus-infected chicken embryo fibroblasts.

We report here a study of the mechanisms leading to loss of growth control in chicken embryo fibroblasts transformed by Rous sarcoma virus (RSV). We have been particularly concerned with the role of the src gene in this process, and have used RSV mutants temperature sensitive (ts) for transformation to investigate the nature of the growth regulatory lesion. The two principal findings were (1) the stationary phase of the cell cycle (G1) in chick embryo fibroblasts seems to have two distinct regulatory compartments (using the terminology of Brooks et al. we refer to these as 'Q' and 'A' states). When rendered stationary at 41.5 degrees C by serum deprivation, normal cells enter a Q state, but cells infected with the ts-mutant occupy an A state. (2) Whereas normal cells can occupy either state depending on culture conditions, the ts-infected cells, at 41.5 degrees C, do not seem to enter Q even though a known src gene product, a kinase, is reported to be inactive at this temperature. We discuss the possibility that viral factors other than the active src protein kinase influence growth control in infected cultures.

Animals↗

PubMed1979

Analysis of the src gene of sarcoma viruses generated by recombination between transformation-defective mutants and quail cellular sequences.

Tumors were produced in quails about 2 months after injection with a transformation-defective mutant of the Schmidt-Ruppin strain of Rous sarcoma virus, subgroup A (SR-A), that retains a small portion of the src gene. Sarcoma viruses were isolated from each of five such tumors. A transformation-defective mutant which has a nearly complete deletion of the src gene was unable to induce tumors. The avian sarcoma viruses recovered from quail tumors (rASV-Q) had biological properties similar to those of the avian sarcoma viruses previously acquired from chicken tumors (rASV-C); these chicken tumors had been induced by the same transformation-defective mutants. Both rASV-Q and rASV-C transformed cells in culture with similar focus morphology and produced tumors within 7 to 14 days after injection into chickens or quails. The size of rASV-Q genomic RNA was indistinguishable from that of SR-A by polyacrylamide gel electrophoresis. The sequences of rASV-Q RNA genomes were analyzed and compared with those of the parental transformation-defective virus, SR-A and of rASV-C by RNase T1 fingerprinting and oligonucleotide mapping. We found that the src sequences of all five isolates of rASV-Q were identical to each other but different from those of SR-A and rASV-C. Of 13 oligonucleotides of rASV-Q identified as src specific, two were not found in either SR-A or rASV-C RNA. Furthermore, some oligonucleotides present in SR-A or rASV-C or both were absent in rASV-Q. No differences were found for the sequences outside the src region in any of the viruses examined. In addition, rASV-Q-infected cells possessed a 60,000-dalton protein specifically precipitable by rabbit serum raised against SR-D-induced tumors. The facts that the src sequences are essentially the same for rASV's recovered from one animal species and different for rASV's obtained from different species provide conclusive evidence that cellular sequences of normal birds were inserted into the viral genome and supplied to the resulting recombinant viruses genetic information for cell transformation.

Alpharetrovirus↗

PubMed1982

Evidence the pp60src, the product of the Rous sarcoma virus src gene, undergoes autophosphorylation.

pp60src, the product of the rous sarcoma virus src gene, was purified greater than 100,000-fold by a combination of ion-exchange and immunoaffinity chromatography. Incubation of pp60src purified in this fashion with [32P-gamma]ATP resulted in a single 32P-labeled protein when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Staining of these gels with silver nitrate showed a predominant 60,000-dalton polypeptide which comigrated with the protein labeled with 32P in vitro. Partial digestion of this protein with V8 protease after in vitro iodination indicated that it was pp60src. These results suggest that pp60src is able to autophosphorylate.

Avian Sarcoma Viruses↗

PubMed1995

Differing kinase activity of the c-yes and c-src gene proteins in TPA-induced megakaryocytic differentiation of T-33 and K562 cell lines.

We examined the protein kinase (PK) activity of the c-yes and c-src gene proteins (c-YES, c-SRC) at an early phase of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced megakaryocytic differentiation of T-33 and K562 cells with use of immunoprecipitation and in vitro kinase assay. We found that c-SRC PK activity of TPA-treated T-33 and K562 cell lines had been enhanced compared with the untreated ones, but in contrast, no enhancement of c-YES PK activity by the TPA treatment was observed in these cell lines. We also examined PK activity in TPA-induced monocytic differentiation of U937 monoblastic cells that exhibited no megakaryocytic markers and found that both the c-YES and c-SRC PK activity was enhanced by the TPA treatment. Our data suggest that c-YES and c-SRC play different and unique roles in TPA-induced megakaryocytic differentiation in T-33 and K562 cells.

Cell Differentiation↗

PubMed1983

Correlation between tumor-specific surface antigens and src gene expression in Rous sarcoma virus-induced rat tumors.

Immunization with Rous sarcoma virus (RSV)-induced mouse tumors or with SR-3Y1 or NY8-3Y1 rat fibroblasts transformed by a wild type RSV or an env gene deletion mutant of RSV induced complete transplantation resistance against an RSV-induced mouse tumor (CSA1M) in syngeneic hosts. On the other hand, 10 of 19 mice immunized with ts68-3Y1 rat fibroblasts transformed by an src gene temperature-sensitive mutant of RSV (permissive temperature: 33-35 degrees C) could not reject the CSA1M. SR-3Y1, NY8-3Y1 and RSV-induced mouse tumors expressed a common tumor-specific cell-surface antigen (TSSA) detected by a syngeneic rat antiserum against NY8-3Y1. In ts68-3Y1, expression of the TSSA was temperature-sensitive, TSSA being detected only when ts68-3Y1 was cultivated at the permissive temperature. Immunoprecipitation showed that serum from a rabbit bearing an RSV-induced tumor detected a 60-kdalton protein in cell extracts from SR-3Y1 and NY8-3Y1. Antiserum to NY8-3Y1 failed to detect this protein. These results suggest that the tumor-specific surface antigen(s) on RSV-induced mammalian tumors was coded for by an RSV src gene that was not identical with the simple form of the 60-kdalton protein identified.

Animals↗

PubMed1999

Absence of genetic alteration at codon 531 of the human c-src gene in 479 advanced colorectal cancers from Japanese and Caucasian patients.

Activation of c-src, a cellular human gene homologous in sequence to the v-src gene of Rous sarcoma virus, had been thought to play an important role in the progression of several types of human cancers, without having undergone any genetic changes. However, recently truncating mutations at codon 531 of the c-src gene were reported in 12% of the advanced colon cancers, and it was also demonstrated that this change was activating, transforming, tumorigenic, and metastasis promoting. To investigate whether the codon 531-specific mutation could be involved in the carcinogenesis of colorectal cancer in the Japanese and Caucasian populations, we examined a total of 479 advanced colorectal cancers from 421 Japanese patients (46 of them with liver or lung metastases) and from 58 Caucasian patients (11 of them with liver metastases). Using the PCR-RFLP assay and additional single-strand conformation polymorphism analysis, we detected no genetic alteration in any of the advanced colorectal cancers. Our results suggest that the codon 531-specific mutational activation of c-src is unlikely to play a significant role in the malignant progression of colorectal cancers among most Japanese and Caucasian patients.

Asian People↗

PubMed1985

No expression of a Rous sarcoma virus-induced tumor antigen in mammalian cells infected with retroviruses transducing other oncogenes of the src gene family.

Immunization with mouse and rat cells transformed by Rous sarcoma virus (RSV) or by B77 avian sarcoma virus (ASV) induced complete transplantation resistance against an RSV-induced mouse tumor (CSA1M) in syngeneic hosts. In contrast, most of the mice immunized with a Fujinami sarcoma virus-transformed rat fibroblast line (FSV-3Y1), a feline sarcoma virus-transformed cat fibroblast line (FeSV-FEF), an Abelson leukemia virus-infected Balb/3T3 cell line (AbLV-3T3), or an uninfected 3Y1 cell line could not reject the CSA1M. Serologic analysis with the use of a complement-dependent cytotoxicity assay supported the results of transplantation studies. The mouse and rat cells transformed by RSV or B77 ASV expressed a common tumor-specific cell surface antigen (TSSA) detected by syngeneic antiserum against the CSA1M, whereas none of the FSV-3Y1, FeSV-FEF, and AbLV-3T3 cells expressed the TSSA. These results suggest that the common TSSA in the mouse and rat cells transformed by RSV or B77 ASV containing src gene is not shared with mammalian cells infected with retroviruses transducing other oncogenes of the src gene family (i.e., fps, fes, and abl).

Animals↗

PubMed1978

Characterization of Rous sarcoma virus src gene products synthesized in vitro.

The cell-free synthesis of three major proteins from virion RNA of nondefective Rous sarcoma virus (RSV), but not from RNA of transformation-defective deletion mutants, has been observed. The apparent molecular weights of these transformation-specific proteins are approximately 60,000 (60K), 25K, and 17K. Tryptic maps of methionine-containing peptides revealed the 17K, 25K, and 60K proteins to be overlapping in sequence. However, only partial homology was observed between the 17K, 25K and 60K proteins synthesized from Schmidt-Ruppin strain, subgroup D, RSV RNA and those synthesized from Prague strain, subgroup B, RSV, RNA. About half of the methionine peptides in the Schmidt-Ruppin strain, subgroup D, 60K protein were shared with the Prague strain, subgroup D, 60K protein, and the rest were distinct to each. The virion RNAs coding for the 60K, 25K, and 17K proteins were found to be polyadenylated and to sediment with maximal mRNA activity at about 23, 19 to 20, and 18S, respectively. In addition, transformation-specific proteins with molecular weights of 39K and 33K were observed by in vitro synthesis. These proteins are also related to the 60K, 25K, and 17K proteins and were synthesized from polyadenylated RSV RNA of approximately 21 to 22S. RNase T1-resistant oligonucleotides were analyzed in parallel, and the src-specific oligonucleotides were found to be first present in equimolar amounts in those gradient fractions sedimenting at 21 to 22S. Our data suggest that synthesis of the 60K protein is initiated near the 5' terminus of the src gene, whereas the 39K, 33K, 25K, and 17K proteins are initiated internally in the src gene. All of these proteins appear to be initiated independently, but they may have a common termination site.

Avian Sarcoma Viruses↗

PubMed1980

Adhesion plaques of Rous sarcoma virus-transformed cells contain the src gene product.

Another intracellular location of the Rous sarcoma virus (RSU) src gene product (pp60src) has been detected within RSV-transformed cells by indirect immunofluorescence. By using rabbit anti-tumor serum specific for pp60src, a speckled pattern of fluorescence was found on the ventral surface of RSV (Schmidt-Ruppin strain)-transformed normal rat kidney cells. Several tests indicated that this pattern was specific for pp60src. In addition, interference-reflection microscopy was used to visualize cellular adhesion plaques, which are the points at which cells attach to the substratum. Simultaneous immunofluorescence and interference-reflection microscopy indicated that the speckles of pp60src fluorescence corresponded exactly to the adhesion plaque structures. The presence of pp60src within the adhsion plaques was further demonstrated by indirect immunofluorescences on isolated adhesion plaques that remained bound to glass after removal of the cells. pp60src also was observed in adhesion plaques of RSV-tranformed chicken embryo fibroblasts (CEF) and mouse fibroblasts, as well as CEF infected with the temperature-sensitive RSV mutant tsNY68 and grown at permissive temperature. At nonpermissive temperature, pp60src was not detectable in adhesion plaques of the tsNY68-infected CEF. Adhesion plaques serve as focal points of microfilament bundle attachment, and thse results suggest that pp60src interacts directly with cellular cytoskeletal components.

Animals↗

PubMed1996

Sequence variation in the src gene product affects metastasis formation: the central, but not exclusive, role of the tumor immune response.

Sequence variation in the src gene product could, in principle, influence metastasis formation through either of 2 effects: an alteration in tumor antigenicity or a non-immune-mediated change in one or more src-associated functions. Our present results establish that both mechanisms underlie the difference in relative levels of metastasis formation induced by the v-src vs. the c-src(527) oncogene. A point that emerges from this analysis is the segregation, within a chicken line genotypically uniform at the major histocompatibility (B) complex (MHC), of a phenotype defined by strong resistance to secondary v-src-induced tumor challenge. The pattern of segregation is consonant with the possibility that a gene unlinked to the MHC governs immune response levels to v-src-encoded tumor antigen.

Animals↗

PubMed1978

Induction of DNA synthesis in terminally differentiated myotubes by the activation of the src gene of Rous sarcoma virus.

Mononucleated myogenic cells from 11-day-old chicken embryos were infected with tsLA24 or tsNY68, temperature-sensitive transformation mutants of Rous sarcoma virus. The infected mononucleated myogenic cells were incubated at the nonpermissive temperature (41 degrees C) and allowed to develop into multinucleated myotubes. These myotubes have withdrawn from the cell cycle, and no DNA synthesis was observed as long as the cultures were maintained at the nonpermissive temperature. However, when the incubation temperature of these cultures was lowered to the permissive temperature (36 degrees C) for expression of the src gene, DNA synthesis was induced in multinucleated myotubes. For this induction of DNA synthesis, cells infected with tsLA24 had to be incubated at the permissive temperature for at least 50 hr, while the induction of DNA synthesis in cells infected with tsNY68 required less than 20 hr. Induction of DNA synthesis was observed by autoradiography as well as by measuring incorporation of [3H]thymidine into the macromolecule fraction in these myotube cultures. For the maintenance of capacity to induce DNA synthesis, constant presence of the src gene product is necessary, because when the temperature of these cultures was returned to 41 decrees C, the myotubes lost the capacity to induce DNA synthesis. During the process of DNA induction one biochemical marker of muscle (creatine kinase) remained unchanged.

Animals↗

PubMed1987

Primary sequence and developmental expression of a novel Drosophila melanogaster src gene.

We have sequenced a cDNA clone for the Drosophila melanogaster gene Dsrc28C, a homolog of the vertebrate gene c-src. The cDNA contains a single open reading frame encoding a protein of 66 kilodaltons which contains features highly conserved within the src family of tyrosine protein kinases. Novel structural features of the Dsrc28C protein include a basic pI and a polyglycine domain near the amino terminus. Cell-free translation of in vitro-transcribed RNA yielded a protein of the predicted size which could be immunoprecipitated by anti-v-src antisera. RNA blot hybridization revealed that the gene is expressed predominantly during embryogenesis, in imaginal disks of third-instar larvae, and in adult females. In situ hybridization showed that expression in adult females is largely confined to nurse cells and developing oocytes.

Amino Acid Sequence↗

PubMed1984

Enhancement of cellular src gene product associated tyrosyl kinase activity following polyoma virus infection and transformation.

We examine the interaction between polyoma-virus-encoded middle tumor antigen and the cellular src gene product, pp60c-src, using a series of monoclonal antibodies that recognize mammalian pp60c-src. Our results show that infection of mouse cells with transformation-competent strains of polyoma virus results in the stimulation of pp60c-src kinase activity severalfold over that observed in uninfected mouse cells and mouse cells infected with transformation-deficient polyoma virus. A similar degree of enhancement of pp60c-src kinase activity was found in polyoma-virus-transformed rodent cells. No differences were detected in the level of pp60c-src synthesis in polyoma-virus-infected and uninfected mouse cells or polyoma-virus-transformed and normal rodent cells. These studies demonstrate that polyoma-virus-encoded middle tumor antigen is associated with pp60c-src in lysates of polyoma-virus-infected and polyoma-virus-transformed cells and suggest a novel mechanism for the functional activation of a cellular proto-oncogene product, namely, that the interaction between middle tumor antigen and pp60c-src leads to a stimulation of pp60c-src tyrosyl kinase activity.

Animals↗

PubMed1994

Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity.

We have generated mice with targeted disruptions of the src-like genes hck and fgr to assess the role of these kinases in myeloid cell development and function. Hematopoiesis appears to proceed normally in both hck-l- and fgr-l- animals, and in hck-l(-)-fgr-l- double homozygotes, but phagocytosis is impaired in hck-l- macrophages. Macrophages cultured from doubly homozygous, hck-l(-)-fgr-l- animals retain many other normal functional properties, suggesting that the deficiency of these kinases is complemented by other src family members. The specific activity of the Lyn protein kinase is increased in hck-l- macrophages, implying that Lyn may compensate for a deficiency in Hck. Doubly mutant animals, however, have a novel immunodeficiency characterized by an increased susceptibility to infection with Listeria monocytogenes, indicating that either hck or fgr is required to maintain a normal natural immune response. These data provide the first direct example of genetic interactions between src gene family members.

Animals↗

PubMedDate not supplied

[Transcription and expression in Escherichia coli of src gene cloned sequences of rous sarcoma virus].

Effective transcription of virus-specific sequences was shown in Escherichia coli cells that carry recombinant plasmids pPrC11 and psrcC with fragments of the Rous sarcoma virus (RSV) genome. Analysis of transcripts revealed several classes of RNA, one of which is probably transcribed from the structural part of the RSV src gene. Analysis of the primary structure of the region adjacent to the src RSV gene showed the existence of sequences similar to the bacterial promoters from which the src-specific RNAs can be transcribed. The synthesized RNA directs the translation of a functionally active protein product, that has tyrosine-specific phosphoproteinkinase activity.

Avian Sarcoma Viruses↗

PubMed1989

The two Xenopus laevis SRC genes are co-expressed and each produces functional pp60src.

The haploid genome of Xenopus laevis contains two src genes, and transcripts from both genes are found in the maternal RNA pool of the oocyte (Steele, R. E. (1985) Nucleic Acids Res. 13, 1747-1761). We have now isolated cDNA clones which contain complete coding sequences from both src mRNAs. In vitro translation of RNAs transcribed in vitro from these clones produces in each case a protein with an apparent molecular mass of 57 kDa. The in vitro-synthesized proteins show identical protease cleavage patterns. Sequence analysis of the coding regions of the two cDNAs revealed that they both produce 532-amino acid polypeptides which differ from each other at only eight sites. Analysis of silent site changes between the two coding sequences suggests that the two genes began diverging about 25 million years ago. Hybridization with probes specific for each of the two src RNAs indicates that the two genes are co-expressed in embryos and in at least some adult tissues as well as during oogenesis. Finally, expression of each of the cDNA clones in yeast causes the appearance of proteins which are recognized by an antibody which binds to phosphotryosine.

Amino Acid Sequence↗

PubMed1994

New case of c-src gene transduction: the generation of virus PR2257.

PR2257 is a new replication-defective avian sarcoma virus which harbours in addition to the spliced version of the c-src gene also about 950 bp of no-coding cellular sequences located downstream from the c-src stop codon (Geryk et al., 1989). Comparison of the 950 bp region transduced by PR2257 with the chicken c-src cDNA (Dorai et al., 1991) and genomic sequences of the c-src 3' non-coding region from chicken and quail has shown that there are no additional introns. The c-src 3' non-coding region represents the largest c-src exon (No. 12) comprising about 2 kb. Absence of conserved open reading frames within this region in chicken and quail genomic DNAs excludes the possibility for coding a protein by these sequences. Also, the possibility was excluded that numerous endogenous virus-derived sequences identified in molecularly cloned PR2257 provirus played a role in the c-src transduction. After serial passaging of PR2257 virus in vivo a variant PR2257/16 was isolated. In PR2257/16, the size of the env gene was increased due to homologous recombination with a helper virus. In addition to mutations in the viral leader and the v-src coding region, a large deletion in transduced c-src 3' non-coding sequences was found in the PR2257/16 genome. The significance of genome modifications for selective advantage of this viral variant in vivo is discussed.

Animals↗