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PubMed1981

MHC gene control of growth of avian sarcoma virus-induced tumours in chickens: a study on the role of virus strains.

A comparison was made of growth patterns (progression/regression) of tumours induced by different strains of avian sarcoma virus in two partially congenic inbred lines of chickens homozygous for different MHC haplotypes. In each instance studied, the ability to regress tumours was shown to be a dominant trait controlled by MHC-linked genes. The results also demonstrate a difference in growth pattern between tumours induced by different strains of virus in an inbred line as well as different growth patterns of tumours induced by the same strain of virus in the two inbred lines. We conclude that the MNC-linked resistance gene is part of a polymorphic genetic region and, in addition, that there is immunogenic heterogeneity of the viral gene product expressed on tumour cells induced by closely related viral strains which is relevant to tumour regression. We suggest that the product of the src gene, p60src, is a plausible candidate for the immunogenic target of the MHC-linked rejection response.

Animals↗
PubMed1991

Cell division is required for expression of v-myc transforming properties in chicken embryonic neuroretina cells.

We previously reported that avian retroviruses carrying the v-myc oncogene alone fail to induce sustained proliferation and transformation of non-dividing chicken neuroretina (CNR) cells from 7-day-old embryos. However, v-myc is capable of transforming CNR cells which have been induced to multiply by the v-mil oncogene. These results suggest that entry into the cell cycle is required for the transformation of CNR cells by v-myc. To further assess the role of cell division, we investigated the transforming properties of v-myc in CNR cells conditionally induced to divide by the v-src gene or by modified culture conditions. We show that v-myc transforms CNR cells infected with Rous sarcoma virus mutants which induce cell proliferation in the absence of transformation. Expression of these transforming properties in CNR cells infected with temperature-sensitive v-src mutants depends on the continuous mitogenic activity of p60v-src. We also report that v-myc is able to transform CNR cells and to increase their growth potential under culture conditions which allow transient multiplication of uninfected cells. However, these v-myc-transformed cells rapidly cease to divide when returned to culture conditions that restrict the growth of normal cells. Taken together, these results indicate that transformation of CNR cells by the v-myc oncogene continuously depends on their ability to enter the cell cycle.

Animals↗
PubMed2000

The Src/Csk regulatory circuit arose early in metazoan evolution.

We have identified a gene encoding a member of the Csk family of non-receptor protein-tyrosine kinases (PTKs) in the early-diverging metazoan Hydra. In situ hybridization analysis of the distribution of RNA from the Hydra Csk gene indicates that it is expressed in most of the epithelial cells of the adult polyp and in gametogenic cells. Comparison of the expression pattern of Hydra Csk with that of STK, the Hydra Src gene orthologue, reveals that the two genes are largely co-expressed. Such co-expression is consistent with a role for Hydra Csk in regulation of STK activity. This possibility was tested directly by coexpressing Hydra Csk with STK in yeast. Co-expression suppressed the growth inhibition seen when STK alone is expressed in yeast. Suppression was dependent on the presence of the putative regulatory tyrosine in the carboxyl-terminal tail of STK. Phosphotyrosine immunoblot analysis confirmed that expression of Csk resulted in suppression of STK kinase activity. Taken together these data indicate that the regulatory circuit involving Src and Csk PTKs was established prior to the divergence of the phylum Cnidaria from the rest of the metazoans.

Animals↗
PubMed1989

Mutations in polyomavirus middle T antigen affecting tumorigenesis.

P155 is a polyomavirus mlt mutant with normal transforming ability but impaired tumorigenic potential. The mutation, a 12-bp deletion (nucleotides 1348-1359), removes amino acids 372 to 375 from middle T and affects its ability to function in tumorigenesis (C. Gelinas, S. Masse, and M. Bastin, 1984, J. Virol. 51, 242-246). We used deletion loop mutagenesis to introduce point mutations within the wild-type sequence spanned by the P155 deletion. A mutant phenotype resembling that of P155 could be produced by as little as one alanine to valine substitution at residue 373. The mutants were impaired in their ability to induce tumors in rats but they could still transform established cell lines or primary fibroblasts in culture. To define the biochemical defect, we examined the mutant middle T antigen both for association with pp60c-src, the cellular src gene product, as well as its pattern of phosphorylation. No obvious differences explaining the phenotype were observed. The mutant middle T associated with, and activated pp60c-src, but exhibited a slightly altered pattern of phosphorylation, presumably because of additional sites on the middle T protein.

Animals↗
PubMed1981

Genetic structure, transforming sequence, and gene product of avian sarcoma virus UR1.

We analyzed the genetic structure and gene products of the newly isolated avian sarcoma virus UR1, which recently has been shown to be replication defective and to contain no sequences homologous to the src gene of Rous sarcoma virus. The sizes of the genomic RNAs of UR1 and its associated helper virus, UR1AV, were determined to be 29S and 35S (5.9 and 8.5 kilobases), respectively, by gel electrophoresis and sucrose gradient sedimentation. RNase T1 oligonucleotide mapping of purified viral RNAs indicated that UR1 RNA contains eight unique oligonucleotides in the middle of the genome and shares four 5'-terminal and three 3'-terminal oligonucleotides with UR1AV RNA. The unique sequences of UR1 and Fujinami sarcoma virus were found to be closely related to each other by molecular hybridization of UR1 RNA with DNA complementary to the unique sequence of Fujinami sarcoma virus RNA, but minor differences were found by oligonucleotides fingerprinting. In the regions flanking the unique sequences, UR1 and Fujinami sarcoma viral RNAs contain distinct oligonucleotides, which are shared with oligonucleotides of the respective helper viral RNAs. Cell transformed with UR1 produce a single 29S RNA species which contains a UR1 unique sequence; this species is most likely the mRNA coding for the transforming protein. In UR1-transformed cells, a phosphoprotein fo 150,000 daltons (p150) was detected by immunoprecipitation with antiserum against gag proteins. p150 was associated with a protein kinase activity that was capable of phosphorylating p150 itself, immunoglobulin G of antiserum, and a soluble substrate, alpha-casein. This enzyme transferred phosphate exclusively to tyrosine residues of substrates in vitro, but p 150 labeled in vivo with 32P contained both phosphoserine and phosphotyrosine. The in vitro kinase reaction was not affected by the presence of cyclic AMP or cyclic GMP and strongly preferred Mn2+ over Mg2+. Thus, the properties of UR1 protein are almost identical to those of Fujinami sarcoma virus protein.

Alpharetrovirus↗
PubMed1986

Intracellular localization and processing of pp60v-src proteins expressed by two distinct temperature-sensitive mutants of Rous sarcoma virus.

The transforming protein of Rous sarcoma virus, pp60v-src, is known to be a tyrosine protein kinase, but the mechanism of cell transformation remains unclear. In further investigating pp60v-src structure and function, we have analyzed two temperature-sensitive (ts) Rous sarcoma virus src gene mutants, tsLA29 and tsLA32. The mutations in tsLA29 and tsLA32 map in the carboxy-terminal region and the amino-terminal half of pp60v-src, respectively, and encode mutant proteins with either temperature-labile (tsLA29) or -stable (tsLA32) kinase activities. Here we examined the intracellular processing and localization of these pp60v-src mutants and extended our characterization of transformation parameters expressed by cells infected by the Rous sarcoma virus variants. No obvious defects in functional integrity of the tsLA32 pp60v-src could yet be demonstrated, whereas the tsLA29 pp60v-src was perturbed not only in kinase activity, but also in aspects of protein processing and localization. Analysis of transformation parameters expressed by infected cells demonstrated the complete temperature lability of both mutants.

Actinin↗
PubMed1992

Tyrosine phosphorylation of a 120,000 dalton membrane-associated protein by the neural form of pp60c-src, pp60c-src+.

The c-src proto-oncogene encodes a 60,000 dalton tyrosine kinase, pp60c-src, which is the prototype member of the family of non-receptor tyrosine kinases. A neural-specific form of pp60c-src, pp60c-src+, is detected only in neurons of the central nervous system. pp60c-src+ contains a six amino acid insert (neural insert) in the SH3 region that is generated by alternative splicing. Previous reports indicate that the profiles of proteins phosphorylated on tyrosine in chick embryo fibroblast (CEF) cells by pp60c-src+ or pp60c-src are equivalent. In this report, the activities of pp60c-src+ and pp60c-src, as well as the activated variants, pp60(527F+) and pp60(527F), were compared in CEF cells by examining the steady-state levels of tyrosine phosphorylation of several known pp60src substrates. Most substrates examined were phosphorylated on tyrosine to equivalent levels in CEF cells expressing either the neural- or fibroblast-specific src gene products. However, the relative extent of tyrosine phosphorylation of a 120 kDa protein (p120) was increased in cells expressing the neuronal forms of either c-src or c-src527F. The increased tyrosine phosphorylation of p120 did not appear to be caused by the neural insert facilitating a specific interaction between pp60c-src+ and p120. These data indicate that preferential phosphorylation of p120 in neural cells may contribute to the specialized function of pp60c-src+ in neural cells.

Animals↗
PubMed1980

Molecular events in cells transformed by Rous Sarcoma virus.

The Rous sarcoma virus (RSV) transforming gene product has been identified and characterized as a phosphoprotein with a molecular weight of 60,000, denoted pp60src. Partially purified pp60src displays a closely associated phosphotransferase activity with the unusual specificity of phosphorylating tyrosine residues in a variety of proteins. That the enzymatic activity observed is actually encoded by the RSV-transforming gene is indicated by the comparison of the pp60src-protein kinase isolated from cells tranformed by a wild-type RSV or by a RSV temperature-sensitive transformation mutant; these experiments revealed that the latter enzyme had a half-life of 3 min at 41 degrees C, whereas that of the wild-type enzyme was 20 min. Evidence is now beginning to accumulate showing that viral pp60src expresses its protein kinase activity in transformed cells as well as in vitro because at least one cellular protein has been identified as a substrate for this activity of pp60src. Although the protein kinase activity associated with pp60src is itself cyclic AMP (cAMP) independent, the molecule contains at least one serine residue that is directly phosphorylated by the cellular cAMP-dependent protein kinase, thus suggesting that the viral transforming gene product may be regulated indirectly by the level of cAMP. The significance of this latter observation must be regarded from the point of view that the RSV src gene is apparently derived from a normal cellular gene that seemingly expresses in normal uninfected cells a phosphoprotein structurally and functionally closely related to pp60src. This celluar protein, found in all vertebrate species tested, also is a substrate for a cAMP-dependent protein kinase of normal cells, and, therefore, may be evolved to function in a regulatory circuit involving cAMP.

Animals↗
PubMed1983

Immunological study of a cellular 35K phosphorylated polypeptide detected in Rous sarcoma virus transformed cells.

We have immunoprecipitated a phosphoprotein of 35K daltons (35K) common to RSV-transformed chick embryo fibroblasts (CEF) and rodent cells. The phosphorylation of this antigen depends on the expression of the v-src gene and contains phosphotyrosine. The pre-existing 35K protein, of CEF infected de novo, was further shown to become phosphorylated shortly after the appearance of active pp60v-src, and about 1 day before morphological transformation. The experiments with RSV-transformed rodent cells have shown that the 35K phosphoprotein is associated with the cellular framework. Another phosphoprotein of 37K was found in the RSV-transformed rodent cells, but not in the transformed CEF. However, this protein was not phosphorylated at tyrosine residues and its phosphorylation persisted, at the restrictive temperature, in cells transformed by a ts mutant of RSV.

Animals↗
PubMed1988

pp60v-src tyrosine kinase is expressed and active in sarcoma-free avian embryos microinjected with Rous sarcoma virus.

Early embryonic avian tissue is resistant to transformation by Rous sarcoma virus. To determine the nature of this resistance, we examined the expression and properties of the Rous sarcoma virus transforming protein pp60v-src, in infected embryonic chicken limbs in ovo. Lysates from Rous sarcoma virus-infected limbs contained the viral structural protein p19gag, as detected by immunoblot analysis, and showed pp60v-src kinase activity in vitro. Immunoblot analysis of lysates with anti-phosphotyrosine antibodies revealed a number of phosphotyrosine-containing proteins present in lysates of Rous sarcoma virus-infected embryos but not in lysates of control, uninfected embryos. Anti-phosphotyrosine immunoreactivity was observed in frozen sections in the same cell types that expressed pp60v-src and p19gag. These studies demonstrate that pp60v-src is co-expressed with viral structural determinants in infected embryonic avian tissue. Furthermore, pp60v-src is active in ovo as a tyrosine-specific phosphotransferase, despite the apparent lack of sarcoma induction. The localization pattern of the major src gene substrate p36 (calpactin I) was compared with that of p19gag by double-label immunofluorescence and found to be generally nonoverlapping. These observations are consistent with the concept that the induction of tumors in ovo requires complementation between viral determinants and host factors. These host factors, which may be critical substrates of pp60v-src, are subject to developmental regulation in the avian embryo.

Animals↗
PubMed1993

Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells.

Malignant astrocytoma is the most common primary human brain tumor. Most astrocytomas express a combination of platelet-derived growth factor (PDGF) and PDGF receptor which could close an autocrine loop. It is not known whether these autocrine loops contribute to the transformed phenotype of astrocytoma cells or are incidental to that phenotype. Here we show that dominant-negative mutants of the PDGF ligand break the autocrine loop and revert the phenotype of BALB/c 3T3 cells transformed by the PDGF-A or PDGF-B (c-sis) gene. Then, we show that these mutants are selective in that they do not alter the phenotype of 3T3 cells transformed by an activated Ha-ras or v-src gene or by simian virus 40. Finally, we show that these mutants revert the transformed phenotype of two independent human astrocytoma cell lines. They have no effect on the growth of human medulloblastoma, bladder carcinoma, or colon carcinoma cell lines. These observations are consistent with the view that PDGF autocrine loops contribute to the transformed phenotype of at least some human astrocytomas.

3T3 Cells↗
PubMed1991

The different activation of int genes in mammary carcinomas developed in three mouse strains harboring mouse mammary tumor viruses derived from DD/Tbr.

RNA expressions of common integration site (int) genes and several oncogenes were investigated in mammary carcinomas spontaneously developed in different three strains of mice; DD/Tbr, NIH Swiss and BALB/c which harbor DD-MMTV derived from DD/Tbr mouse. Latter two strains of mice were designated NIH/Mtv+ and BALB/Mtv+, respectively. An increased expression of int-1 (wnt-1) and int-2 genes was observed in 56% (9/16) and 50% (8/16) of mammary carcinomas of DD/Tbr mice, respectively. Either int-1 or int-2 RNAs were expressed in 81% (13/16) of the carcinomas of DD/Tbr mice. IN NIH/Mtv+ mice, activation of int-1 and int-2 was observed in 41% (7/17) and 24% (4/17) of mammary carcinomas, respectively. Either int-1 or int-2 RNAs were expressed in 47% (8/17) of the carcinomas examined in this strain. In BALB/Mtv+ mice, on the other hand, either int-1 or int-2 gene were transcribed into RNAs at low frequency (33%: 3/9). These results suggest that the frequency of activation of int genes in mammary carcinomas induced by the same DD-MMTV in three strains of mice is genetically defined characteristics of these strains, and that the involvement of int-1 and int-2 genes in virus-induced mammary carcinogenesis may be influenced by genetic properties of animals. The activation of int-1 and int-2 genes did not clearly correlate with an increase in the expression of oncogenes examined; H-ras, K-ras, N-ras, myc, raf, fgr, fms, erB, mos, and src genes.

Animals↗
PubMed1983

Molecular events leading to fusiform morphological transformation by partial src deletion mutant of Rous sarcoma virus.

A mutant of the Prague strain of Rous sarcoma virus (RSV) has two deletions near the 5'-terminus of its src gene. The mutant (dl 5) induced fusiform morphological transformation in chick embryo fibroblasts (CEF) in contrast to the round type morphological transformation induced by wild type (wt) RSV. The partially deleted src of dl5 was shown to code for a 52K protein which has tyrosine kinase activity as high as that of p60src. In dl 5-transformed cells, a 36K protein was heavily phosphorylated, while two proteins (MW = 55K and 57K) were dephosphorylated to the same extent as compared with cells transformed by wt RSV. The relative abundance of phosphotyrosine in vinculin was almost the same in both dl 5- and wt RSV-transformed cells after extended passage of dl 5-transformed cells without marked changes in their morphology. On the other hand, the amounts of vinculin and fibronectin in dl 5-transformed cells were twice those in wt RSV-transformed cells, although less than the amounts in uninfected cells. These results suggest that events leading to cellular morphological transformation are neither directly correlated with phosphorylation of the 36K protein, with dephosphorylation of the 55K and 57K proteins, nor with the level of phosphorylation of tyrosine residues in vinculin, but rather are correlated with the amount of vinculin and fibronectin.

Animals↗
PubMed1976

Changes in microfilament organization and surface topogrophy upon transformation of chick embryo fibroblasts with Rous sarcoma virus.

A series of morphological changes occurred when chick embryo fibroblasts infected with the NY68 mutant of Rous sarcoma virus were shifted from nonpermissive temperature (41degrees) to permissive temperature (37 degrees). We observed three distinct stages in cell morphology and surface topography that were correlated with a reduction in the organization and assembly of actin-containing microfilament bundles. Our observations suggest that control of microfilament organization and surface topography are responsive to the presence of a functioning transforming gene (src) product of Rous sarcoma virus.

Actins↗
PubMed1986

Transformation by p60src with altered N-terminal sequences.

The transforming activity of the src gene product of Rous sarcoma virus, p60src, depends on both tyrosine specific protein kinase activity and N-terminal myristylation that is required for the plasma membrane association of this protein. The src proteins of two recovered avian sarcoma viruses, rASV157 and rASV1702, are exceptional in that they are not myristylated and yet are active in transformation. These viruses also induce tumors that regress rapidly. We found that their src proteins have unusual N-terminal structures: 30-45 amino acids of the env signal peptide are attached to internal (6th and 76th) amino acids in the src sequences. These altered N-terminal structures seem to be responsible for many abnormal properties of these mutant src proteins, including the early regression of tumors they induce.

Amino Acid Sequence↗
PubMed1997

Myogenin expression is necessary for commitment to differentiation and is closely related to src tyrosine kinase activity in quail myoblasts transformed with Rous sarcoma virus.

Quail myoblasts transformed with a temperature-sensitive mutant of Rous sarcoma virus (QM-RSV cells) proliferate at 35.5 degrees C, a permissive temperature for RSV, but differentiate at 41 degrees C, a nonpermissive temperature, with the formation of multinucleated myotubes and the synthesis of muscle-specific proteins. Tyrosine kinase activity of the src gene product derived from RSV is closely related to regulation of this temperature-dependent differentiation, and the cells obtain commitment to differentiation by incubation for about 12 h at 41 degrees C with dephosphorylation of tyrosine-phosphorylated protein(s). It was examined how myogenin, a member of myogenic regulatory factors, participates in commitment to differentiation and tyrosine dephosphorylation of QM-RSV cells. Myogenin was expressed within 8 h and reached a plateau within 10 h at 41 degrees C. Each cell clone whose differentiation proceeded faster or slower than the parental QM-RSV cells was reflected by a faster or slower myogenin expression, corresponding to the time that is required for commitment to differentiation. It was suggested that there is a lag time between myogenin expression and the acquisition of commitment in QM-RSV cells. On the other hand, at 35.5 degrees C, a condition which suppresses differentiation, myogenin expression was not detected. However, herbimycin A, an inhibitor of protein tyrosine kinase, induced myogenin expression even at 35.5 degrees C. On the contrary, myogenin expression was inhibited at 41 degrees C by sodium orthovanadate, an inhibitor of tyrosine-phosphorylated protein phosphatase. Furthermore, forced induction of myogenin into the cells cultured at 35.5 degrees C resulted in the formation of multinucleated myotubes and the synthesis of muscle-specific proteins. These results suggest that myogenin expression is one of the indispensable conditions for the acquisition of commitment to differentiation and is regulated by tyrosine phosphorylation and dephosphorylation of some protein(s) in QM-RSV cells.

Animals↗
PubMed1981

Rat sarcoma virus: further analysis of individual viral isolates and the gene product.

Rasheed rat sarcoma virus, derived by in vitro cocultivation of two rat cell lines (Rasheed et al., Proc. Natl. Acad. Sci. U.S.A. 75:2972-2976, 1978), has been reported to code for a protein of 29,000 Mr, immunologically related to the 21,000 Mr src gene product of Harvey and Kirsten sarcoma viruses. Rat sarcoma virus p29 was thought to contain at least part of a rat type C virus structural protein, since antiserum prepared against whole rat virus was able to immunoprecipitate rat sarcoma virus p29 but not Harvey or Kirsten sarcoma virus p21 (Young et al., Proc. Natl. Acad. Sci. U.S.A. 76:3523-3527, 1979). We now report that antiserum directed against rat type C virus p15, but not viral p12, p10, or p27, immunoprecipitated rat sarcoma virus p29. The p15 antiserum was also able to immunoprecipitate both denatured p29 and a peptide derived by V-8 protease cleavage of p29, indicating that this antiserum contains antibodies directed against primary amino acid determinants. Finally, five separate isolates of rat sarcoma virus were found to code for p29, which indicates that a highly specific site of recombination is involved in the generation of sarcoma viruses in rat cells.

Animals↗