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PubMed1987

NH2-terminal sequences of two src proteins that cause aberrant transformation.

Two isolates of recovered avian sarcoma viruses (rASVs), rASV157 and rASV1702, transform cells in culture, but have greatly reduced in vivo tumorigenicity. The src proteins of rASV157 and rASV1702 have alterations within their NH2 termini, are not myristoylated, and have an altered subcellular localization. We have molecularly cloned and determined the nucleotide sequences of the src genes of rASV157 and rASV1702. We found that their src proteins have unusual NH2 termini: the rASV157 src protein NH2 terminus consists of 30 amino acids of the env signal peptide attached to Ser-6 of the src sequence, while the rASV1702 src protein NH2 terminus consists of 45 amino acids of the env signal peptide attached to Ala-76 of the src sequence. Expression of recombinant Rous sarcoma virus constructs containing the molecularly cloned rASV src genes produced src proteins with the same properties as those of the parental viruses. Our results suggest that the NH2-terminal structures are responsible for many unusual properties of the mutant src proteins.

Amino Acid Sequence↗
PubMed1987

Expression of Rous sarcoma virus transforming protein pp60v-src in Saccharomyces cerevisiae cells.

The Rous sarcoma virus (RSV) pp60v-src protein was expressed in Saccharomyces cerevisiae cells either from a plasmid vector carrying the v-src gene or in yeast cells containing a single-copy v-src gene chromosomally integrated. In both yeast strains, v-src gene transcription is regulated by the galactose-inducible GAL10 promoter. Growth in galactose-containing medium resulted in constitutive expression of pp60v-src in the integrated strain and transient expression of higher levels of pp60v-src in the plasmid-bearing strain. The concentration of pp60v-src in the plasmid-bearing strain at its peak of expression was approximately threefold lower than that found in RSV-transformed mammalian cells. pp60v-src synthesized in yeast cells was phosphorylated in vivo on sites within the amino and carboxyl halves of the molecule. In immune complex kinase assays, the yeast pp60v-src was autophosphorylated on tyrosine and was able to phosphorylate exogenous substrates such as casein and enolase. The specific activity of pp60v-src synthesized in yeast cells was approximately 5- to 10-fold higher than that made in mammalian cells. Induction of pp60v-src caused the death of the plasmid-bearing yeast strain and transient inhibition of growth of the single-copy strain. Concomitantly, this induction resulted in high levels of tyrosine phosphorylation of yeast cell proteins. This indicates that pp60v-src functions as a tyrosine-specific phosphotransferase in yeast cells and suggests that hyperphosphorylation of yeast proteins is inimical to cell growth.

Avian Sarcoma Viruses↗
PubMed2006

Structural features of incremental line-like striations in mandibular condylar cartilage of c-src-deficient mice.

Mandibular condylar cartilage is sensitive to masticatory force, while mice lacking the c-src gene (c-src-deficient mice) have osteopetrosis and tooth eruption failure. The purpose of this study was to investigate the morphology of the mandibular condyle in these mice, which were maintained with a soft-food diet for 240 days after birth. The condylar head in the c-src-deficient mice showed slight deformity in shape before weaning, but showed remarkable undergrowth after weaning. No significant morphological or histological differences were detected between the mandibular condyle in wild-type mice fed soft food and those fed hard food, indicating that osteopetrosis, as well as abnormal masticatory force, influences the morphology of the mouse mandibular condyle, and that malocclusion rather than dietary consistency may have greater influence. After 70 days, incremental line-like striations consisting of cartilaginous and non-cartilaginous layers were detected in the mandibular condyle of the c-src-deficient mice, but not in the tibial growth plate. Immunostaining of aggrecan, collagen types II and X, and osteopontin was detected in the cartilaginous layers, but not in the non-cartilaginous layers showing collagen type I immunostaining. Chondrocyte lacunae were not eroded in the cartilaginous layers, and complete circumferential mineralisation around the lacunae and impaired osteoclast (chondroclast) function can account for this phenomenon. However, repeated cessation of chondrocyte differentiation may be required to completely explain the formation of the striations. These results indicate that the mandibular condyle in the c-src-deficient mice has unique structural features, adding to its deformity.

Aggrecans↗
PubMed1991

[The detection of the c-src protein gene product in human lung tumors].

Immunoblotting and immunochemistry were used to study the expression of a c-src gene-encoded protein in human lung tumors. The authors were the first to identify this otherwise rarely expressed protooncogene in as many as 60% of lung malignancies of various histogenesis. The expression of c-src protein was increased not only in neuroendocrine tumors (small-cell cancer and atypical carcinoid) but also in non-small-cell tumors such as adenocarcinoma, bronchoalveolar and squamous-cell lung cancer. A weak correlation between protein expression and degree of cell differentiation was established for squamous-cell tumors. The study failed to identify the oncoprotein in the normal tissue and benign lesions. Immunoblotting using Mab 327 monoclonal antibodies and the immunohistochemical method employing TBR polyclonal serum yielded similar data. To summarize, an increased expression of pp60c-src was observed in lung cancer of various histology.

Antibodies, Monoclonal↗
PubMed1989

Differential expression of N-myc and c-src proto-oncogenes during neuronal and schwannian differentiation of human neuroblastoma cells.

Neuroblastoma (NB) cells can be induced to differentiate bidirectionally into either neuronal or schwannian cells by different inducers. However, the underlying mechanisms are poorly understood. We examined the expression of N-myc and c-src genes in 3 human NB-cell lines during either neuronal or schwannian differentiation in vitro, since proto-oncogenes are considered to play a pivotal role in regulating cell proliferation and differentiation. Decreased N-myc expression and increased c-src expression were observed during neuronal differentiation by retinoic acid, polyprenoic acid (E5166) and dibutyryl cyclic AMP, whereas the expression of N-myc and c-src genes was considerably reduced during schwannian differentiation by bromodeoxyuridine, demonstrating that the expression of N-myc and c-src genes was regulated independently in the bipolar differentiation processes of NB cells. Our results suggest that enhanced N-myc expression might be closely linked to the undifferentiated phenotypes of NB cells, that c-src expression might be related to the neuronal differentiation of NB cells, and that N-myc and c-src genes might be regulated independently in the determination of the bipolar differentiation of NB cells.

Cell Differentiation↗
PubMed2003

Identification of the SRC pyrimidine-binding protein (SPy) as hnRNP K: implications in the regulation of SRC1A transcription.

The human SRC gene encodes pp60(c-src), a non-receptor tyrosine kinase involved in numerous signaling pathways. Activation or overexpression of c-Src has also been linked to a number of important human cancers. Transcription of the SRC gene is complex and regulated by two closely linked but highly dissimilar promoters, each associated with its own distinct non-coding exon. In many tissues SRC expression is regulated by the housekeeping-like SRC1A promoter. In addition to other regulatory elements, three substantial polypurine:polypyrimidine (TC) tracts within this promoter are required for full transcriptional activity. Previously, we described an unusual factor called SRC pyrimidine-binding protein (SPy) that could bind to two of these TC tracts in their double-stranded form, but was also capable of interacting with higher affinity to all three pyrimidine tracts in their single-stranded form. Mutations in the TC tracts, which abolished the ability of SPy to interact with its double-stranded DNA target, significantly reduced SRC1A promoter activity, especially in concert with mutations in critical Sp1 binding sites. Here we expand upon our characterization of this interesting factor and describe the purification of SPy from human SW620 colon cancer cells using a DNA affinity-based approach. Subsequent in-gel tryptic digestion of purified SPy followed by MALDI-TOF mass spectrometric analysis identified SPy as heterogeneous nuclear ribonucleoprotein K (hnRNP K), a known nucleic-acid binding protein implicated in various aspects of gene expression including transcription. These data provide new insights into the double- and single-stranded DNA-binding specificity, as well as functional properties of hnRNP K, and suggest that hnRNP K is a critical component of SRC1A transcriptional processes.

Amino Acid Sequence↗
PubMed1998

Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene.

The in vivo biological function of a steroid receptor coactivator was assessed in mice in which the SRC-1 gene was inactivated by gene targeting. Although in both sexes the homozygous mutants were viable and fertile, target organs such as uterus, prostate, testis, and mammary gland exhibited decreased growth and development in response to steroid hormones. Expression of RNA encoding TIF2, a member of the SRC-1 family, was increased in the SRC-1 null mutant, perhaps compensating partially for the loss of SRC-1 function in target tissues. The results indicate that SRC-1 mediates steroid hormone responses in vivo and that loss of its coactivator function results in partial resistance to hormone.

Animals↗
PubMed2000

Role of Src expression and activation in human cancer.

Since the original identification of a transmissible agent responsible for the development of tumors in chickens, now known to be a retrovirus encoding the v-src gene, significant progress has been made in defining the potential functions of its human homolog, SRC. The product of the human SRC gene, c-Src, is found to be over-expressed and highly activated in a wide variety of human cancers. The relationship between Src activation and cancer progression appears to be significant. Moreover, Src may have an influence on the development of the metastatic phenotype. This review discusses the data supporting a role for c-Src as a critical component of the signal transduction pathways that control cancer cell development and growth, and provides the rationale for targeting Src in drug discovery efforts.

Antineoplastic Agents↗
PubMed2000

Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac.

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.

Adrenergic beta-Agonists↗
PubMed1980

Evidence for the common origin of viral and cellular sequences involved in sarcomagenic transformation.

The src genes of six different strains of avian sarcoma virus (ASV) were compared with those of a series of newly isolated sarcoma viruses, termed "recovery avian sarcoma viruses" (rASV's). The rASV's were isolated recently from chicken and quail tumors induced by transformation-defective (td) deletion mutants of Schmidt-Ruppin Rous sarcoma virus. The RNase T1-resistant oligonucleotide maps were constructed for the RNA genomes of different strains of ASV and td mutants. The src-specific sequences, characterized by RNase T1-resistant oligonucleotides ranging from 9 to 19 nucleotides long, were defined as those mapping between approximately 600 and 2,800 nucleotides from the 3' polyadenylate end of individual sarcoma viral RNAs, and missing in the corresponding td viral RNAs. Our results revealed that 12 src-specific oligonucleotides were highly conserved among several strains of ASV, including the rASV's, whereas certain strains of ASV were found to contain one to three characteristic src-specific oligonucleotides. We previously presented evidence supporting the idea that most of the src-specific sequences present in rASV RNAs are derived from cellular genetic information. Our present data indicate that the src genes of rASV's are closely related to other known ASVs. We conclude that the src genes of different strains of ASV and the cellular sarc sequences are of common origin, although some divergence has occurred among different viral src genes and related cellular sequences.

Alpharetrovirus↗
PubMed2000

An alternative, human SRC promoter and its regulation by hepatic nuclear factor-1alpha.

The SRC gene encodes the proto-oncogene pp60(c-)(src), a tyrosine kinase implicated in numerous signal transduction pathways. In addition, the SRC gene is differentially expressed, developmentally regulated, and frequently overexpressed in human neoplasia. However, the mechanisms regulating its expression have not been completely explored. Here we describe the isolation of a new distal SRC promoter and associated exon, designated 1alpha, which we mapped to a position 1.0 kilobase upstream of the previously described SRC1A housekeeping promoter. Differential use of these promoters and their associated exons coupled with subsequent splicing to a common downstream exon results in c-Src transcripts with different 5' ends but identical coding regions. Promoter analysis following transient transfections into HepG2 cells mapped the minimal 1alpha promoter to a region 145 bp upstream of the major transcription start site. This region contained a consensus binding site for hepatic nuclear factor-1 (HNF-1), a liver-enriched transcription factor implicated in the regulation of a number of genes in liver, kidney, stomach, intestine, and pancreas. Subsequent mobility shift assays confirmed that HNF-1alpha isoform was the predominant factor interacting with this region of the promoter. Mutation of the HNF-1 site resulted in a dramatic reduction in SRC promoter activity. Cotransfection studies demonstrated the promoter could be strongly transactivated by the HNF-1alpha isoform but not by the related HNF-1beta factor. Consistent with these results, we demonstrated that transcripts originating from the SRC1alpha promoter display a tissue restricted pattern of expression with highest levels present in stomach, kidney, and pancreas. These results indicate that SRC transcriptional regulation is much more complex than previously realized and implicates HNF-1 in both the tissue-specific regulation of the SRC gene in normal tissues and the overexpression of c-Src in certain human cancers.

Base Sequence↗
PubMed1992

Characterization of the promoter region of the src family gene lyn and its trans activation by human T-cell leukemia virus type I-encoded p40tax.

The src family gene lyn is expressed preferentially in B lymphocytes but very little in normal T lymphocytes. Transcription of the lyn gene in T lymphocytes was shown to be induced by the p40tax protein encoded by human T-cell lymphotropic virus type I. For determination of the mechanism of p40tax-mediated trans activation, the transcriptional promoter region of the lyn gene was characterized. By endonuclease S1 mapping, the transcriptional initiation sites were identified within the 770-bp EcoRI-SacI fragment of the 5'-terminal portion of the human lyn gene. This fragment showed promoter activity when placed upstream of the bacterial chloramphenicol acetyltransferase gene and transfected into various cell lines. Nucleotide sequence analysis revealed that the lyn promoter region contained four GC box-like sequences but not a TATA or CCAAT box. In addition, it contained sequences characteristic of a cyclic AMP-responsive element, octamer-binding motif, PEA3-like motifs, and NF kappa B-binding motif-like sequence. Mutational analysis suggested that the octamer-binding motif sequence is of primary importance for the lyn promoter activity but that the other elements are not. Cotransfection of various chloramphenicol acetyltransferase constructs containing different length of the lyn promoter together with p40tax expression plasmids into Jurkat T cells showed that the sequence responsible for p40tax-induced transcription is present around the transcription initiation sites.

Base Sequence↗
PubMed1989

Structure and expression of STK, a src-related gene in the simple metazoan Hydra attenuata.

Both cDNA clones and a genomic DNA clone encoding a 509-amino-acid protein that is 64% similar to chicken pp60c-src were isolated from the simple metazoan Hydra attenuata. We have designated this gene STK, for src-type kinase. Features of the amino acid sequence of the protein encoded by the STK gene suggest that it is likely to be myristoylated and regulated by phosphorylation in a manner similar to that found for pp60c-src. The genomic sequence encoding the protein was found to be interrupted by at least two introns, one of which was located in a position identical to that of one of the introns in the chicken src gene. The STK gene was expressed during early development of H. attenuata and at high levels in the epithelial cells of adult polyps. Probing of Hydra proteins with an antibody to phosphotyrosine indicated that the major phosphotyrosine-containing protein in H. attenuata may be the STK protein itself. H. attenuata is the simplest organism from which a protein-tyrosine kinase gene has been isolated. The presence of such a gene in the evolutionarily ancient phylum Cnidaria suggests that protein-tyrosine kinase genes arose concomitantly with or shortly after the appearance of multicellular organisms.

Amino Acid Sequence↗
PubMed1989

Identification of a phorbol ester-repressible v-src-inducible gene.

Chicken embryo fibroblasts (CEF) infected with a temperature-sensitive Rous sarcoma virus (RSV) mutant, tsNY72-4, express a set of pp60v-src-induced RNAs soon after shift to the permissive temperature. By subtractive and differential screening, we have cloned 12 of these sequences, 2 of which were c-fos and krox-24. Serum induced all the v-src-inducible genes tested, suggesting that these genes serve roles in normal cell division and are not specific to transformation per se. Significantly, however, v-src produced prolonged, and in some cases kinetically complex, patterns of induction compared to serum. For most of the clones, phorbol 12-tetradecanoate 13-acetate (TPA) induced mRNAs with kinetics similar to that of serum. However, one clone (CEF-4) was expressed in a biphasic manner. Another (CEF-10) was repressed by TPA at 1 hr, after which this mRNA was permanently induced. The pattern of repression-induction of CEF-10 mRNA is the inverse of protein kinase C (PKC) activity in the cell, suggesting that PKC actively represses this gene. In vivo expression of CEF-10 mRNA is restricted predominantly to the lung. A full-length CEF-10 cDNA encodes a 41-kDa protein that has an amino-terminal signal peptide for secretion, contains a markedly high number of cysteine residues, and shows no sequence similarity to known proteins.

Amino Acid Sequence↗
PubMed1984

Overexpression of the c-src protein does not induce transformation of NIH 3T3 cells.

NIH 3T3 mouse cells were transfected with plasmids that induce efficient expression of either (i) the Rous sarcoma virus v-src gene, (ii) the chicken c-src gene, or (iii) a recombinant gene combining the 5' portion of c-src with the 3' end of v-src. Focus formation in tissue culture and formation of large colonies in soft agar did not occur in cells transfected with c-src. Cells transfected with c-src expression plasmids did not form foci but were isolated using a coselectable biological marker. They display morphological and substrate-independent growth characteristics intermediate between those of normal and v-src-transformed mouse cells, and lysates from these cells have enhanced in vitro tyrosine kinase activity. Transfection with the c-src-v-src recombinant induced focus formation with an efficiency similar to that obtained with a v-src expression plasmid. These results imply that v-src-induced transformation does not result just from overexpression of an essentially normal cellular protein but, at least in part, depends on the mutations distinguishing the cellular and viral proteins.

Amino Acid Sequence↗
PubMed1977

Role of surface modulating assemblies in growth control of normal and transformed fibroblasts.

Cellular microtubules, microfilaments, and surface receptors have been postulated to form a surface modulating assembly that regulates surface receptor mobility and cell growth. To test this hypothesis, we examined three agents known to affect cell growth [colchicine, concanavalin A (Con A), and the src gene product of Rous sarcoma virus] for their effects on chick embryo fibroblasts. Individual cells from serum-starved normal fibroblast populations became committed to enter S phase at various times over a 12 hr period after exposure to serum. Colchicine and other microtubule-disrupting agents blocked entry into S phase at a point close to the commitment point for each cell. The lectin Con A also blocked entry into the S phase when present in doses sufficient to modulate surface receptor mobility. In contrast, succinyl-Con A, which does not induce surface modulation, had no effect. Both Con A and colchicine blocked the appearance of cytoplasmic factors capable of stimulating DNA replication in a cell-free system. To study endogenous effects on the surface modulating assembly, we infected fibroblasts with a Rous sarcoma virus (tsNY68) having a temperature-sensitive mutation in the transforming (src) gene. We have previously shown that microtubular and microfilamentous structures of the surface modulating assembly are direct or indirect targets of the src gene product with consequent reduction in the capacity of Con A to induce surface modulation. TsNY68-infected fibroblasts shifted to the non-permissive temperature acquired normal microtubular morphology more rapidly (2 hr) than cells grown at the permissive temperature in the presence of protein synthesis inhibitors (7.5 hr). This suggests that the src gene product acts directly on the surface modulating assembly rather than via the nucleus or at the level of protein synthesis. Furthermore, "transformation" of the surface modulating assembly was partly blocked by treatment of the infected cells with Con A but not succinyl-Con A. Both Con A and colchicine inhibited entry into the S phase following a shift from nonpermissive to permissive growth conditions. All of these observations are in accord with the hypothesis that the surface modulating assembly acts as a signal regulator in growth control.

Animals↗
PubMed1985

Immunohistochemical detection of the gene product of Rous sarcoma virus in human brain tumors.

We have studied 108 cases of brain tumors by immunohistochemical staining utilizing an antiserum against the src gene product and GFA protein in order to elucidate the relationship between the brain tumors and the transforming genes. While the normal human brain tissues were not positive with the antiserum against the src gene product, several astrocytomas were clearly positive and other brain tumors were negative with the same. Src-gene product related peptide was detected in some of the human astrocytomas.

Astrocytoma↗
PubMed1986

Isolation and oncogenic potential of a novel human src-like gene.

We have isolated cDNA molecules representing the complete coding sequence of a new human gene which is a member of the src family of oncogenes. Nucleotide sequence analysis revealed that this gene, termed slk, encoded a 537-residue protein which was 86% identical to the chicken proto-oncogene product, p60c-src, over a stretch of 191 amino acids at its carboxy terminus. In contrast, only 6% amino acid homology was observed within the amino-terminal 82 amino acid residues of these two proteins. It was possible to activate slk as a transforming gene by substituting approximately two-thirds of the slk coding sequence for an analogous region of the v-fgr onc gene present in Gardner-Rasheed feline sarcoma virus. The resulting hybrid protein molecule expressed in transformed cells demonstrated protein kinase activity with specificity for tyrosine residues.

Amino Acid Sequence↗