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PubMedDate not supplied

Differential effects of phorbol ester on tumor cells induced by avian sarcoma virus.

Avian sarcoma virus-induced tumors usually grow progressively for several weeks and then regress. We have injected phorbol myristate acetate (PMA) directly into tumors in an effort to stimulate neoplastic growth. The results show instead that PMA exerted an inhibitory effect in this regard and, in fact, caused an acceleration of tumor regression. At the same time, treatment of cultured avian sarcoma cells with PMA resulted in greatly diminished levels of the kinase activity associated with the src gene product, pp60src. PMA-treated tumor cells from regressing sarcomas were, however, stimulated to express viral antigens at their surface and produced more progeny virus than did untreated tumor cells.

Animals↗
PubMed1995

Production and characterization of monoclonal antibodies against the recombinant p50csk protein tyrosine kinase: a tool for signal transduction research.

p50csk is a protein tyrosine kinase (PTK) that has been reported to regulate the activity of other PTKs belonging to the src gene family. Several hybridoma clones that produce monoclonal antibodies (MAbs) directed against recombinant p50csk were established. Five of the clones were analyzed for their ability to recognize native and denatured p50csk protein after undergoing native and denaturing polyacrylamide gel electrophoresis followed by western blotting. In addition, the clones were tested for their ability to immunoprecipitate p50csk and yet maintain tyrosine kinase activity of antibody-bound p50csk. None of the clones cross-reacted with pp60c-src, a PTK that shares with p50csk the homologous SH1 catalytic domain and SH2 and SH3 regulatory domains. These MAbs can be used to study p50csk directly, and its role in regulating members of the src family.

Animals↗
PubMed1978

Genesis of a virus-transforming gene.

The gene src responsible for neoplastic transformation of fibroblasts by avian sarcoma viruses was apparently derived from highly conserved nucleotide sequences in the normal avian genome. The cellular homologue of src is unlinked to the genome of an endogenous virus in chicken cells and functions in an unknown manner during normal cell metabolism.

Alpharetrovirus↗
PubMed1981

A mouse homolog to the avian sarcoma virus src protein is a member of a protein kinase cascade.

Recent work has identified a cascade of membrane bound protein kinases in Ehrlich ascites tumor cells. These enzymes, designated PKL, PKS and PKM, are present in both Ehrlich tumor and mouse brain, but the cascade is active only in the tumor tissue. We have now purified a fourth protein kinase, PKF, that is also associated with this cascade. Protein kinase F prosphorylates PKL and is phosphorylated by PKS. The position of this kinase in the cascade is as follows, where the arrows denote phosphorylation: [Formula: see text] The phosphorylation by PKF, like phosphorylation by the other kinases, is at a tyrosine residue and causes the substrate kinase (PKL) to become active. The role of the tyrosine phosphorylation in activating these kinases is described in detail elsewhere. One result of activation of the cascade is the phosphorylation of the beta subunit of the Na+K+-ATPase, which causes inefficient Na+ pumping and is at last in part responsible for the high aerobic glycolysis of Ehrlich ascites tumor cells. By several criteria protein kinase F from Ehrlich cells is homologous to the src gene product (pp60src) from avian sarcoma viruses. Antiserum raised against PKF and sera from rabbits bearing rous sarcoma virus (RSV)-induced tumors quantitatively precipitate the same 60 kd phosphoprotein from cell lysates of three different RSV-transformed cell lines. Both proteins phosphorylate PKL and a 130 kd cytoskeletal protein (vinculin). The tryptic maps of these proteins are closely similar. Both proteins bind specifically to PKL covalently coupled to Sepharose. We used this latter observation to facilitate the purification of pp60 src from RSV-transformed cells.

Amino Acids↗
PubMed1979

Structural studies on oncornavirus-related sequences in chicken genomic DNA: two-step analyses of EcoRI and Bgl I restriction digests and tentative mapping of a ubiquitous endogenous provirus digests and tentative mapping of a ubiquitous endogenous provirus.

DNA from a variety of uninfected chicken cell types has been analyzed by using restriction endonuclease digestion and RPC-5 ion-exchange chromatography followed by agarose gel electrophoresis. Endogenous retrovirus sequences were detected by using a 32P-labeled avian leukosis viral RNA probe. One simple pattern was identified in an individual containing unexpressed endogenous proviral genes (gs-chf-phenotype for group-specific antigens and chicken helper factor) that was common to all individuals studied. A tentative restriction has been derived for this and one other gs-chf-endogenous provirus. Other gs-chf-individuals and individuals with other phenotypes (e.g., gs+ chf+ and gsl chlfhE) showed more complicated patterns that often included additional bands and thus probably additional proviruses. RNA from an avian sarcoma virus was used to detect cellular sequences (sarc) homologous to the viral transforming gene (src). Results have revealed that a single restriction endonuclease EcoRI fragment of 13 x 10(6) daltons contains the majority of these sequences and confirm that they are not adjacent to the endogenous provirus.

Animals↗
PubMed2025

Investigating the molecular mechanism of Yangxin decoction in treating major depressive disorder using network pharmacology and molecular docking technology approaches.

Yangxin decoction has been used to treat major depressive disorder (MDD). This study aims to identify the active components and potential mechanisms of Yangxin decoction in treating MDD using network pharmacology and molecular docking technology. The active components and targets of Yangxin decoction were screened, and MDD-related targets were predicted. Networks of "herbal medicine-active components-potential targets" and protein-protein interaction were constructed. Core components and core targets were identified through network topology analysis. Gene ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on candidate genes. Molecular docking was conducted using AutoDock software (Olson Laboratory of the Scripps Research Institute, San Diego) to explore the interactions between core targets and active components, and the results were visualized using PyMOL (DeLano Scientific LLC, South San Francisco). A total of 433 active components and 392 targets of Yangxin decoction were identified, along with 11,796 MDD-related targets. There were 680 overlapping targets between Yangxin decoction and MDD, associated with 104 active components. Core targets identified through network topology analysis and molecular docking included serine/threonine kinase 1 (AKT1), tumor necrosis factor, interleukin-6, tumor protein P53, and proto-oncogene tyrosine-protein kinase Src. Gene ontology enrichment analysis revealed 1606 biological processes, 191 cellular components, and 373 molecular functions. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified 212 signaling pathways, with significant enrichment in caffeine metabolism, bladder cancer, advanced glycation end products-receptor for advanced glycation end products signaling pathway in diabetic complications, and vascular endothelial growth factor signaling pathway. Molecular docking results showed strong binding energy between core active components and core targets. Yangxin decoction exhibits multi-component, multi-pathway, and multi-target therapeutic characteristics. It primarily regulates targets such as AKT1, tumor necrosis factor, interleukin-6, tumor protein P53, and proto-oncogene tyrosine-protein kinase Src through advanced glycation end products-receptor for advanced glycation end products, vascular endothelial growth factor, and ErbB signaling pathways, exerting anti-inflammatory, immune-regulating, and oxidative stress-inhibiting effects to alleviate MDD.

Molecular Docking Simulation↗
PubMed1993

Protooncogene-encoded protein kinases in interleukin-2 signal transduction.

Protooncogenes are the normal forms of cellular genes that when altered in their expression or coding sequences can contribute to neoplastic transformation. As these genes often are important for normal cellular growth control, we explored the possibility that protein kinases encoded by particular protooncogenes could participate in signal transduction pathways regulated by the T cell growth factor, interleukin-2 (IL-2). In this review we summarize our findings to date regarding Raf-1, a serine/threonine-specific kinase that becomes phosphorylated on tyrosine residues and enzymatically activated in response to IL-2 stimulation. In addition, we describe our investigations of Lck and Lyn, two closely related protein tyrosine kinases of the src gene family that physically associate with the IL-2 receptor complex and whose activities are regulated by IL-2 in at least some T cells and B cells, respectively.

Animals↗
PubMed1987

Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src.

A murine retroviral vector, LSNLsrc, has been constructed and examined for its ability to induce growth factor independence in cells normally dependent on interleukin 2 (IL-2) or interleukin 3 (IL-3) for growth. The LSNLsrc vector coexpressed the v-src gene of Rous sarcoma virus and the neo gene from transposon Tn5, allowing infected cells to be selected on the basis of G418 resistance. The murine cell lines CTLL-2 and FD.C/1, which are dependent for growth on IL-2 and IL-3, respectively, were both readily infected with the LSNLsrc virus. LSNLsrc-infected, G418-resistant cultures of FD.C/1 cells were able to give rise to IL-3-independent progeny, but all G418-resistant CTLL-2 cells retained normal IL-2 dependence. The induction of IL-3 independence by v-src was not a direct event, since limiting dilution analysis of the LSNLsrc-infected FD.C/1 cells showed that most of them were IL-3 dependent, despite expression of v-src mRNA and active pp60v-src kinase. However, clones selected from this population in the presence of IL-3 were able to undergo a subsequent progression event and generate IL-3-independent progeny. The generation of factor-independent variants in the clonal cultures was a rare event, as witnessed by the death of most of the cells in each clone when IL-3 was withdrawn. Together, these data indicate that a secondary event, in addition to v-src expression, was required to generate IL-3-independent growth. No evidence was found for an autocrine mechanism of transformation involving IL-2, IL-3, interleukin 4, or granulocyte-macrophage colony-stimulating factor.

Cell Division↗
PubMed1984

Autocrine growth induced by src-related oncogenes in transformed chicken myeloid cells.

Chicken myeloid cells transformed by the v-myb-or v-myc-containing leukemia viruses, E26 and OK 10, respectively, require chicken myelomonocytic growth factor (cMGF) for proliferation in vitro. Upon superinfection with retroviruses carrying oncogenes of the src gene family, these myeloid cells acquire the ability to grow in the absence of exogenous cMGF. Conditioned medium prepared from superinfected E26 cells contains a growth-stimulating activity similar in biological and immunological properties to cMGF. This activity is reduced by more than 80% following absorption of conditioned media with antiserum against cMGF. Incubation of superinfected E26 cells with an immunoglobulin fraction of antiserum against cMGF inhibits their proliferation, indicating that the cells are dependent on the secreted factor. We conclude that viral oncogenes of the src family can induce chicken myeloid cells to produce a cMGF-like factor(s) that stimulates proliferation of these cells in an autocrine fashion.

Animals↗
PubMed1987

Purification and properties of a non-histone chromatin protein with a molecular weight of 38,000 daltons specific for transformed rat cells.

Non-histone chromatin proteins prepared from a normal rat cell line (No. 7) and the cells transformed with Rous sarcoma virus (RSV) (s7-1) were compared by means of reverse-phase high performance liquid chromatography (reverse-phase HPLC), followed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The results revealed that several proteins were specifically present in the transformed cell chromatin. A specific non-histone chromatin protein with a molecular weight of 38,000 daltons, 38K protein, was purified as a single species from s7-1 cells. This 38K protein was only detected in the transformed state of the cells transformed with a temperature-sensitive (ts) mutant of the src gene and the mutant cells which showed temperature sensitivity as to the transformation with wild type RSV.

Animals↗
PubMed1985

Inter- and intramolecular interactions of highly purified Rous sarcoma virus-transforming protein, pp60v-src.

We have purified intact pp60v-src, the product of the Rous sarcoma virus src gene, over 2400-fold, based on the phosphorylation of tumor-bearing rabbit IgG. The purification procedure involved detergent extraction of the particulate fraction of the cells and sequential chromatography on hydroxylapatite, butyl agarose, DEAE-Sephacel, ADP-agarose, and Sephacryl S-200. Analysis of the preparation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a single silver-stained band with an apparent molecular weight of 60,000. Our results show that the activities of this preparation were qualitatively similar to those described previously for partially purified pp60v-src. Upon analysis by two-dimensional gel electrophoresis, the purified pp60v-src yielded one major species which migrated to the same position as the least acidic of the three major species detectable in cellular lysates, suggesting that the pp60v-src had been dephosphorylated during the purification procedure. We found that pp60v-src was very prone to aggregation; to maintain it as a monomer both Nonidet P-40 and KCl were required. Under conditions which maintained pp60v-src as a monomer, the rate of autophosphorylation was independent of its concentration and thus proceeded via an intramolecular process. Preincubation of pp60v-src with ATP or GTP as well as nonphosphorylating analogs of ATP or GTP preserved its phosphorylating activity toward alpha-casein whereas its activity was reduced 80% upon preincubation in the absence of nucleotides. We suggest that protection with nucleotides rather than autophosphorylation accounts for the apparent increase in the activity of pp60v-src after incubation of the enzyme with ATP.

Adenosine Triphosphate↗
PubMed1984

Effect of src infection on long-term marrow cultures: increased self-renewal of hemopoietic progenitor cells without leukemia.

Long-term marrow cultures prepared from mice have been infected with a molecular recombinant of Rous sarcoma virus and murine amphitropic leukemia virus. This resulted in introduction of the src gene into the cultured cells and expression of its protein kinase function. The infected cultures displayed an altered balance in the accumulation of cells in different compartments of granulocyte differentiation. There was a dramatic increase in the stem cell (CFU-S) compartment and the committed progenitor cell (GM-CFC) compartment and a decrease in mature granulocytes. The altered balance appears to be caused by intrinsic alterations in the CFU-S and GM-CFC themselves, which increase their "self-renewal" capacity at the expense of cell differentiation. Remarkably, unlike its effects in other systems, src did not produce a neoplastic transformation of the hemopoietic cells.

Animals↗
PubMed1978

Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29.

The retrovirus strain MC29 induces a variety of tumors in chickens, including myelocytomatosis and carcinomas of the kidney and liver. In addition, the virus can transform cultures of embryonic avian macrophages and fibroblasts. We have characterized the genome of MC29 virus and have identified nucleotide sequences that may encode the oncogenic potential ofthe virus. MC29 virus can replicate only with the assistance of a related helper virus. The defect in replication is apparently a consequence of a deletion in one or more viral genes: the haploid genome of the MC29 virus has a molecular weight of ca. 1.7 X 10(6), whereas the genome of the helper virus MCAV has a molecular weight of ca. 3.1 X 10(6). Although MC29 virus transforms fibroblasts in culture, its genome has no detectable homology with the gene src that is responsible for transformation of fibroblasts by avian sarcoma viruses. We prepared radioactive single-stranded DNA complementary to nucleotide sequences present in the genome of MC29 virus but not in the genome of MCAV (cDNA(MC29)). If they are contiguous, these sequences (ca. 1,500 nucleotides) are sufficiently complex to encode at least one protein. Homologous sequences were not detectable in several strains of avian sarcoma viruses or in an endogenous virus of chickens. Our findings confirm and extend recent reports from other laboratories and lead to the conclusion that MC29 virus may contain a previously unidentified gene(s) that is capable of transforming several distinct target cells. The evolutionary origins of this putative gene and its location on the viral genome can be explored with cDNA(MC29).

Alpharetrovirus↗
PubMed1983

Isolation of monoclonal antibodies that recognize the transforming proteins of avian sarcoma viruses.

Thirteen clones of hybrid cells which synthesize antibodies directed against the Rous sarcoma virus (RSV) transforming protein, pp60src, were isolated. Mouse myeloma cells were fused with spleen cells from mice that had been immunized with purified pp60src from bacterial recombinants which direct the synthesis of the RSV src gene. The hybridomas which survived the selection medium were screened by immunoprecipitation of pp60src from 32P-labeled lysates of RSV-transformed cells. Monoclonal antibodies produced by subclones derived from 13 hybridomas recognized pp60src encoded by the Schmidt-Ruppin and Prague strains of RSV and the cellular homolog of pp60src. Antibody from clone 261 had a high affinity for the viral yes gene product, and antibodies from clones 443 and 463 recognized the transforming proteins encoded by viruses containing the related transforming genes fps and ros. Several other clones had a low affinity for the viral yes, fps, and ros gene products which could be detected by in vitro phosphorylation of the transforming proteins after immunoprecipitation with the monoclonal antibody. All of the monoclonal antibodies allowed phosphorylation of pp60src and casein in an immune complex-bound reaction.

Animals↗
PubMed1995

The proto-oncogene c-fgr is expressed in normal mantle zone B lymphocytes and is developmentally regulated during myelomonocytic differentiation in vivo.

The proto-oncogene c-fgr is a member of the c-src gene family of cytoplasmic tyrosine kinases. Previous studies have suggested that it is normally expressed in neutrophils, monocytes, macrophages, and natural killer cells. c-fgr is also expressed in the B cells of certain lymphoproliferative disorders, namely, Epstein-Barr virus-associated lymphoproliferative disease, and in chronic lymphocytic leukemia, but it has not previously been detected in normal or reactive human lymphoid tissue. In this study we have determined the pattern of p55c-fgr protein expression in normal human hematopoietic and lymphoid tissues at the single-cell level using immunohistochemical and immunofluorescent techniques. We show that p55c-fgr expression is developmentally regulated with high-level expression first evident at the myelocyte stage of myeloid differentiation. In addition, we show that p55c-fgr is expressed in circulating B lymphocytes isolated from chronic lymphocytic leukemia patients but is not expressed in normal circulating B lymphocytes. Surprisingly, p55c-fgr is also expressed in a subpopulation of normal B lymphocytes, the mantle zone B lymphocytes. This demonstration that p55c-fgr is expressed in a normal B-lymphocyte subpopulation suggests that its expression in certain B-cell lymphoproliferative disorders may be an indirect consequence of, rather than a primary cause of, the neoplastic transformation process.

B-Lymphocyte Subsets↗
PubMed1977

Translation of 35S and of subgenomic regions of avian sarcoma virus RNA.

Rabbit antiserum monospecific for an internal structural protein, p27, of avian sarcoma viruses (ASV) was found to immunoprecipitate polypeptides with molecular weights (Mr) of 180,000 and 76,000 from cell-free reticulocyte lysates programmed by ASV 35S RNA and also from lysates of ASV-infected cells. In addition, the Mr 180,000 protein was also precipitated by antiserum raised against virion DNA polymerase, suggesting that is a product of the two genes nearest the 5' end of virion 35S RNA. We have also investigated the ability of subgenomic portions of virion RNA to program cell-free protein synthesis. A 10-12S poly(A)-containing fragment of RNA from both nondefective and transformation-defective ASV directed the synthesis of a polypeptide of Mr 29,000 immunologically unrelated to the gs antigens; 20-24S poly(A)-containing RNA from nondefective ASV directed the synthesis of a polypeptide of Mr 60,000 not found when a similar RNA preparation from transformation-defective ASV was translated, suggesting that it is the product of the ASV src gene. These results indicate that internal initiation sites for protein synthesis exist on the 35S RNA genome.

Avian Sarcoma Viruses↗
PubMed1988

Nonmyristoylated p60v-src fails to phosphorylate proteins of 115-120 kDa in chicken embryo fibroblasts.

We have used anti-phosphotyrosine antibodies to identify a large number of tyrosine phosphoproteins in Rous sarcoma virus (RSV)-transformed chicken embryo fibroblasts. Most of these proteins were found in the 100,000 X g supernatant when cells were separated into soluble and particulate fractions; however, one group of proteins, of 115-120 kDa, was found in the particulate fraction. The phosphotyrosine content of the 115- to 120-kDa proteins was greatly reduced in chicken embryo fibroblasts infected with mutants of RSV (NY314 and SD10) encoding nonmyristoylated forms of the viral src gene product that do not associate with cellular membranes. Since RSV mutants NY314 and SD10 do not transform cells, phosphorylation of this group of 115- to 120-kDa membrane proteins may be related to the process of transformation.

Animals↗
PubMed1977

Genetic variation in the RNA transcripts of endogenous virus genes in uninfected chicken cells.

Uninfected cells from two different phenotypes of chicken embryos express significant amounts of endogenous viral information, though they do not produce virus particles. Cells of the phenotype gs(+)chf(+) are positive for both group-specific (gs) antigens and chicken helper factor (chf) activity, whereas cells of a second phenotype, gs(L)chf(+)(h(E)), demonstrate noncoordinate expression of these two viral activities (very low amounts of gs antigens, but extremely high helper activity). RNA from these cells was analyzed to determine the size, genetic content, and relative abundance of virus-specific RNAs in cells of each phenotype. Two major size classes of polyadenylic acid-containing RNA, homologous to the avian leukosis virus genome, were detectable in cells of both types. The larger RNA, which contained most of the sequences of the leukosis virus genome, was of different sizes in the two phenotypes, 31S in gs(+)chf(+) cells but 35S in the noncoordinate cell type. Analysis of the viral RNA with gene-specific complementary DNA probes revealed the following characteristics. (i) The 31S RNA appeared to lack portions of the gag and pol genes. (ii) A smaller RNA species, which sedimented at 21S in both cell types, was a transcript of the 3'-proximal portion of the viral genome, consisting of the env gene and the "common" sequences. (iii) The amount of env-specific RNA in the 21S region was more than six times higher in the noncoordinate cell type than in the gs(+)chf(+) cells; this difference was concordant with the 5- to 10-fold higher chf activity in the noncoordinate cells. (iv) The endogenous viral RNA in uninfected cells and the RNA from Rous-associated virus-0 virions hybridized only partially with DNA complementary to the common region of the Rous-associated virus-2 genome, whereas the RNA of all exogenous viruses tested hybridized almost completely to this complementary DNA. Small amounts of src-specific polyadenylated RNA were also present in uninfected chicken cells. This RNA sedimented as a single peak at 26S and was not covalently linked to any other identifiable virus-specific RNA sequences. The amount of src RNA was the same in the above two types of expression-positive cells and also in cells that were gs(-)chf(-), indicating that the transcription of the cellular sequences homologous to the src gene is independent of the transcription of the other endogenous viral genes.

Animals↗