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PubMed1984

Differential expression of the cellular oncogenes c-src and c-yes in embryonal and adult chicken tissues.

The cellular onc-genes c-src and c-yes are expressed very differently during chicken embryonic development. The c-src mRNA and its translational product are detectable at high levels in brain extracts of chicken embryos and adult chickens, whereas muscle extracts show an age-dependent decrease in the amounts of c-src-specific mRNA and pp60c-src kinase activity. In contrast, the levels of c-yes mRNA in brain, heart, and muscle are relatively low in early embryonic stages and increase later on to values comparable to those found for liver, while in adult animals the pattern of c-yes expression is similar to that of the c-src gene. From the close correlation between the levels of pp60c-src, its enzymatic activity, and its corresponding mRNA at a given stage of development and in given tissues, it appears that the expression of pp60c-src is primarily controlled at the level of transcription. It is suggested that because of the different patterns of expression, the two cellular oncogenes, c-src and c-yes, play different roles in cell proliferation during early embryonic stages as well as in ensuing differentiation processes.

Aging↗
PubMed1999

Sphingosine 1-phosphate stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle. Role of endothelial differentiation gene 1, c-Src tyrosine kinase and phosphoinositide 3-kinase.

We report here that cultured airway smooth muscle cells contain transcripts of endothelial differentiation gene 1 (EDG-1), a prototypical orphan Gi-coupled receptor whose natural ligand is sphingosine 1-phosphate (S1P). This is consistent with data that showed that S1P activated both c-Src and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) in a pertussis toxin (PTX)-sensitive manner in these cells. An essential role for c-Src was confirmed by using the c-Src inhibitor, PP1, which markedly decreased p42/p44 MAPK activation. We have also shown that phosphoinositide 3-kinase (PI-3K) inhibitors (wortmannin and LY294002) decreased p42/p44 MAPK activation. An essential role for PI-3K was supported by experiments that showed that PI-3K activity was increased in Grb-2 immunoprecipitates from S1P-stimulated cells. Significantly, Grb-2 associated PI-3K activity was decreased by pretreatment of cells with PTX. Finally, we have shown that the co-stimulation of cells with platelet-derived growth factor (PDGF) and S1P (which failed to stimulate DNA synthesis) elicited a larger p42/p44 MAPK activation over a 30 min stimulation compared with each agonist alone. This was associated with a S1P-dependent increase in PDGF-stimulated DNA synthesis. These results demonstrate that S1P activates c-Src and Grb-2-PI-3K (intermediates in the p42/p44 MAPK cascade) via a PTX-sensitive mechanism. This action of S1P is consistent with the stimulation of EDG-1 receptors. S1P might also function as a co-mitogen with PDGF, producing a more robust activation of a common permissive signal transduction pathway linked to DNA synthesis.

Animals↗
PubMed1983

Drosophila melanogaster DNA clones homologous to vertebrate oncogenes: evidence for a common ancestor to the src and abl cellular genes.

We have isolated phage clones containing the D. melanogaster sequence homologous to the v-abl oncogene, and two types of phage clones containing sequences homologous to the v-src probe. The D. melanogaster abl clone (lambda Dabl1) and one of the src clones (lambda Dsrc1) hybridize with both v-abl and v-src probes, and both map in situ to the same chromosomal position, 73B, on chromosome arm 3L. The second D. melanogaster src clone (lambda Dsrc2) does not react with the v-abl probe and hybridizes in situ to chromosomal position 64B. The hybridization pattern suggests that the src and abl cellular oncogenes have evolved from a common prototype sequence. The homologous sequences in D. melanogaster exhibit hybridization to regions in the vertebrate v-abl and v-src that are important for kinase activity and transforming potential of the viral gene products.

Animals↗
PubMed1995

Regulation of pre-mRNA processing by src.

BACKGROUND: Changes in gene expression in response to external signals provide a key mechanisms for the regulation of higher eukaryotic cell functions. The importance of transcriptional control in the response of cells to growth factors and cytokines has been extensively documented, but gene expression has also been shown to be controlled at other levels, such as the stability of mRNA in the cytoplasm, its localization and translation. By contrast to transcriptional control, little is known of the contribution of pre-mRNA nuclear processing to the regulation of gene expression, as most of our knowledge of pre-mRNA processing in vivo is indirect, being inferred from comparisons of transcription rates and levels of mRNA accumulation. RESULTS: In this study, we have used as a model the well-characterized maturation pathway of transcripts of the cytokine, tumour necrosis factor beta (TNF beta). We have used the murine TNF beta gene as a reporter for pre-mRNA processing, using a co-transfection approach to investigate whether overproduction of proteins involved in signal transduction influences the processing of TNF beta transcripts. Although transfection of both activated ras and src genes led to an increase in RNA accumulation in the nuclear and cytoplasmic compartments, as expected from their transactivation of the TNF beta expression vector, only src induced a modification of RNA processing. Comparison of several modes of src activation indicated that two distinct effects of src on pre-mRNA processing can be coupled: one involves slowing down splicing and the other allows the export of partially spliced transcripts. These effects can be observed not only on the three introns of TNF beta but also on transcripts from a beta globin expression vector. DISCUSSION: We have characterized how the processing of transcripts of TNF beta and beta globin is regulated by the signal transduction pathway that includes the Src protein, establishing that external signals have the capacity to regulate gene expression at a post-transcriptional level within the nucleus. Src seems to act on a general mechanism of splicing and/or mRNA transport, but its biologically relevant targets are likely to be restricted to genes for which either alternative processing pathways are in competition, or the kinetics of splicing is critical. This regulation could reflect a modulation by Src of the activity of components of the splicing and transport machineries, but could also involve RNA-binding proteins, which have been shown to interact with Src.

3T3 Cells↗
PubMed1998

Characterization of the mouse Src homology 3 domain gene Sh3d2c on Chr 7 demonstrates coexpression with huntingtin in the brain and identifies the processed pseudogene Sh3d2c-ps1 on Chr 2.

Formation of intracellular protein complexes is often mediated by Src homology 3 domain-containing proteins interacting with proline-rich target sequences on other proteins. The Sh3d2c gene or its rat/human orthologs have been implicated in synaptic vesicle recycling due to interaction with dynamin I and synaptojanin in nerve terminals. In a yeast two-hybrid system, association with a huntingtin fragment containing an elongated stretch of polyglutamines was observed recently. By genetic mapping and fluorescence in situ hybridization we demonstrate the localization of Sh3d2c on mouse chromosome 7. A processed pseudogene of Sh3d2c, Sh3d2c-ps1, was identified and mapped to mouse chromosome 2. Using RNA in situ hybridization, we show that Sh3d2c is transcribed in various regions of the brain. The striatum, hippocampus, cortex, basal hypothalamus, brain stem, and cerebellum are the most prominent sites of expression. Because huntingtin and Sh3d2c are coexpressed in most regions of the brain, it can be speculated that there is a link between the association of huntingtin/Sh3d2c and the pathogenesis of Huntington disease.

Animals↗
PubMed1990

Differential control of muscle-specific gene expression specified by src and myc oncogenes in myogenic cells.

Myogenic cells can be transformed in vitro by the introduction of several exogenous viral oncogenes. Transformed myoblasts are prevented from terminal differentiation into myotubes by the continuous expression of oncogenes such as myc and src, chosen as prototypes of nuclear and cytoplasmic oncogenes. A comparative analysis of the relationship between transformation and differentiation in myoblasts and cells belonging to other lineages has led to the proposal that terminal differentiation of myc-transformed quail myoblasts is indirectly prevented by the loss of growth control and that myc-bearing cells remain susceptible to growth regulation by interaction with adjacent normal cells. On the contrary, the src oncogene appears to affect expression of the myogenic programme via a direct mechanism, independent from abnormal growth control. There is increasing evidence for the existence of master regulatory genes that govern and influence muscle development in vivo and myogenic differentiation in vitro. Expression of cytoplasmic oncogenes such as src, ras and polyoma middle T in the mouse myogenic cell line, C2, results in inhibition of biochemical differentiation and a marked down-regulation of the MyoD1 and myogenin genes.

Animals↗
PubMed1992

The c-src tyrosine kinase (CSK) gene, a potential antioncogene, localizes to human chromosome region 15q23----q25.

We have previously reported the cloning of a novel cytoplasmic tyrosine kinase, CSK. This tyrosine kinase has been shown to downregulate the tyrosine kinase activity of the c-src oncoprotein through tyrosine phosphorylation of the c-src carboxyl terminus. Cell transformation by src oncoproteins is caused by several oncogenic mechanisms, which interfere with this phosphorylation. The CSK gene could therefore potentially function as an antioncogene. We have here mapped the CSK gene to 15q23----q25 by in situ hybridization.

CSK Tyrosine-Protein Kinase↗
PubMed1992

Sustained induction of egr-1 by v-src correlates with a lack of fos-mediated repression of the egr-1 promoter.

Serum stimulation of quiescent fibroblasts leads to a transient induction of the transcription factor egr-1. However, the induction of egr-1 by v-src was found to be sustained rather than transient. The proto-oncogene fos has been reported to be co-regulated with egr-1 and to repress serum-induced egr-1 expression. We found that c-fos prevents v-src-induced gene expression regulated by the egr-1 promoter. Thus, the sustained induction of egr-1 by v-src could be explained by a lack of c-fos induction by v-src. Consistent with this hypothesis, egr-1 and c-fos were co-induced by serum, but not by v-src, in Balb/c 3T3 cells; v-src did not induce c-fos expression in these cells. We propose that sustained expression of egr-1 induced by v-src in Balb/c 3T3 cells is due to a lack of c-fos down-regulation of egr-1.

3T3 Cells↗
PubMed1997

A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disorder, representing the most frequent inherited cause of chronic renal failure in children. One of the responsible loci, NPH1 , has been mapped to 2q13. The presence of large homozygous deletions of approximately 250 kb in the majority of affected patients allowed us to define a minimal deletion interval for NPH1 . A BAC contig covering this interval was established. Combination of large scale genomic sequencing, cDNA selection and computer-aided analysis led to the characterization of two transcriptional units. One encodes the already known BENE protein, and the other encodes a novel protein of at least 732 amino acids containing a putative src homology 3 domain. In two patients carrying the large deletion of the NPH1 region on only one allele, two mutations were detected in two independent exons of the novel gene. One consists of a single base deletion, causing a frameshift, and the other is a G-->A substitution in the consensus 5' splice donor site. Both mutations thus potentially generate null mutants. One of these mutations was found to segregate with the disease in the family, and the second appeared to be a de novo mutation. We therefore conclude that this novel gene is a strong candidate for NPH.

Amino Acid Sequence↗
PubMed2004

Development of transgenic mice that inducibly express an active form of c-Src in the epidermis.

Recent work from our laboratory has shown that elevated src kinase activity enhances tumor promotion, malignant progression, and metastasis during multistage skin carcinogenesis. In this study, we have generated "gene-switch" src(530) transgenic mice to further analyze the role of this nonreceptor tyrosine kinase in multistage carcinogenesis. Target transgenic mice that have an activated form of the human c-src (src(530)) gene fused with GAL4 binding sites upstream of the thymidine kinase (TK) promoter were generated. Two lines of epidermis-specific transactivator mice were used that targeted the expression of GLVPc or GLp65 transactivators, fusion molecules containing a truncated progesterone receptor with a GAl4-DNA binding domain, with either a mouse loricrin (ML) or human keratin 14 (HK14) promoter, respectively. The transactivator mice (ML.GLVPc or HK14.GLp65) and the target mice (TK.src(530)) were mated to generate bitransgenic mice, and src(530) transgene expression was induced by topical application of RU486 (mifepristone, a progesterone receptor antagonist). In both ML.GLVPc/TK.src(530) and HK14.GLp65/TK.src(530) bitransgenic mice, histological analysis revealed that only the bitransgenic mice had marked epidermal hyperplasia and hyperkeratosis after treatment with RU486. Neither the nontransgenic mice nor the mice hemizygous for either the transactivator transgene or the target transgene alone showed any response to treatment with RU486. In addition, no differences were observed in the skin of the bitransgenic mice versus nontransgenic littermates without treatment of RU486. Interestingly, in HK14.GLp65/TK.src(530) bitransgenic mice, squamous cell carcinomas (SCCs) arose along the periphery of the area of the punch biopsies in 25% of the bitransgenic mice several weeks after taking the biopsy and subsequent to RU486 treatment. Collectively, the data support a role of c-src activation in epidermal hyperproliferation. Furthermore, the data support the conclusion that src activation can substitute for an initiating event in the presence of a tumor promoting stimulus (i.e., wounding). Finally, inducible src(530) transgenic mice provide a new tool for dissecting the role of src activation in multistage carcinogenesis by allowing temporal control of the expression of this oncogene.

Animals↗
PubMed1990

Myristylation of pp60c-src is not required for complex formation with polyomavirus middle-T antigen.

Middle-T antigen (middle-T), the transforming gene product of polyomavirus, associates with several cellular tyrosine kinases, such as pp60c-src. Complex formation leads to kinase activation and is essential for cell transformation. Middle-T-associated as well as uncomplexed pp60c-src is predominantly found in the plasma membrane. We transfected mouse 3T3 fibroblasts with a mutated c-src gene (2Ac-src), allowing the expression of a protein containing alanine instead of glycine in position 2 of the primary translation product. Contrary to the wild-type c-src gene product, pp60c-src(2A) was not myristylated and accumulated in the cytoplasm instead of being transferred to cellular membranes. The mutant protein was able to associate with middle-T and was activated similarly to the wild-type c-src gene product. Both wild-type and 2A mutant protein were membrane associated upon complex formation with middle-T. This finding suggests that the putative carboxy-terminal membrane anchor sequence of middle-T is sufficient to hold middle-T-associated pp60c-src(2A) in the plasma membrane.

Animals↗
PubMed1996

Isolation of a novel gene down-regulated by v-src.

We have isolated a novel gene which was expressed in normal rat cells, but completely suppressed in cells transformed by v-src. The molecularly cloned cDNA was about 1.8 kb in size, containing an open reading frame composed of 464 amino acid residues. DNA sequence analysis showed that there was no corresponding gene in the data bases. Besides the suppression of gene expression in the v-src transformed cells, its expression was also strongly suppressed in cells transformed by other oncogenes such as v-abl, v-fps, v-mos, v-sis, v-K-ras, and polyomavirus middle T, but not affected in cells transformed by human papillomavirus type 16 E6E7 and polyomavirus large T. We named the gene drs for a gene down-regulated by v-src.

Amino Acid Sequence↗
PubMed1999

Structure and chromosomal locations of mouse steroid receptor coactivator gene family.

The newly recognized steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) belong to a homologous gene family and are important transcriptional mediators for nuclear receptors. Through fluorescence in situ hybridization, we have mapped the mouse SRC-1, SRC-2, and SRC-3 genes to chromosomal locations 12A2-A3, 1A3-A5, and 2H2-H4, respectively. By screening a mouse genomic DNA library, performing long-range polymerase chain reaction and sequencing, we have cloned and characterized the mouse SRC-3 gene. The SRC-3 gene contains 19 exons and spans more than 38 kilobases (kb). Intron sizes are variable. Intron 1 (13.5 kb) and intron 15 (4.6 kb) contribute to almost half the total length of the gene. Among 20 exons identified, exon 10 is the largest (869 bp) and encodes the receptor interaction domain. The start and stop codons for translation are in exon 2 and 20, respectively. The relationship between SRC-3 gene structure and its functional protein domains suggests that many functional domains or subdomains are encoded by individual exons. The correlation between gene structure and alternative splice variants is also discussed. In summary, we have defined the structure of mouse SRC-3 gene and found that the genes in the SRC family are located in different mouse chromosomes. This information is important for developing valuable animal models harboring multiple disruptions of the SRC gene family to study their biological functions.

Animals↗
PubMed1984

Mutagenesis of the region between env and src of the SR-A strain of Rous sarcoma virus for the purpose of constructing helper-independent vectors.

The major goal of these experiments is to derive stable, helper independent, retroviral vectors using the SR-A strain of Rous sarcoma virus. Because src is flanked by direct repeats of 110 bases, both src, and sequences that replace src in vector constructions, are lost at high frequency. We have sought to eliminate this homology in order to stabilize the vectors. One copy of the direct repeat must be retained for the virus to replicate properly. Because the downstream direct repeat is linked to the polypurine tract the entire downstream direct repeat cannot easily be eliminated. We therefore sought to eliminate the upstream direct repeat. Using linkers a series of defined deletions and duplications has been created within the region between env and src. The region is relatively large, 379 bases, and has a complex history (it is derived from three different nucleic acid segments each with a distinct and separate origin). We show here that this region provides no functions essential for growth and, for src expression, provides only a functional splice acceptor. We were able to successfully replace the splice acceptor found in the wild type virus with an unrelated splice acceptor partially derived from a synthetic DNA segment. The final product is a replication competent virus that expresses src, and that lacks the entire upstream repeat. Since src is flanked by ClaI sites in these constructions, src can easily be replaced by other genes. Substituting the Tn5 neo gene for src in this construction yields a virus that expresses the neo gene nonselectively.

Animals↗
PubMed1990

Mutations in src homology regions 2 and 3 of activated chicken c-src that result in preferential transformation of mouse or chicken cells.

src homology regions 2 and 3 (SH2 and SH3) of proteins encoded by src and closely related genes are conserved domains believed to modulate the protein-tyrosine kinase activity of this class of proteins, perhaps through interactions with other proteins. To explore the possibility of using src mutants as probes for such interactions, we have compared mouse NIH 3T3 cells with chicken embryo fibroblasts as host cells for 24 previously described substitution and deletion mutants with lesions in the SH2- and SH3-encoding regions of a transformation-competent allele of chicken c-src. Although several of these mutants are equally competent or equally defective for transformation of the two cell types, four mutants (three of which map within SH3) preferentially transform NIH 3T3 cells, and seven mutants (all of which map within SH2) preferentially transform chicken cells. Some of the SH2 mutants least able to transform mouse cells exhibit augmented transforming activity in chicken cells. In general, the in vitro protein-tyrosine kinase activities of the mutants correlated with transforming activities. Thus, in many cases, the catalytic activity of a mutant protein depended upon the host cell in which the protein was made. Such host-dependent mutants may be especially useful reagents for biochemical and genetic studies of the src gene family.

Animals↗
PubMed1995

Chromosomal localization of the mouse Src-like adapter protein (Slap) gene and its putative human homolog SLA.

Molecules containing Src-homology 2 (SH2) and Src-homology 3 (SH3) domains are critical components of signal transduction pathways that serve to relay signals originating from the cell surface to the interior of the cell. Src-like adapter protein (SLAP) is a recently described adapter protein that binds activated the Eck receptor protein-tyrosine kinase. Although SLAP bears a striking homology to the SH3 and SH2 domains of the Src family of nonreceptor tyrosine kinases, it does not contain a tyrosine kinase catalytic domain. In this report, the Slap gene was mapped by linkage analysis to mouse chromosome 15, while its putative human homolog (SLA) was identified and mapped to human 8q22.3-qter using a panel of somatic cell hybrids.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Differential effects of protein phosphatase 2A on distinguishable intracellular signals initiated by v-Src and mediated by HaRas.

v-Src activates gene expression mediated by serum response elements (SREs) and TPA response elements (TREs). v-Src-induced SRE- and TRE-mediated gene expressions are both dependent upon HaRas. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been implicated in v-Src-initiated signals. We report here that expression of the catalytic subunit of PP2A upregulates v-Src- and v-HaRas-induced TRE-mediated gene expression, whereas PP2A downregulates v-Src- and v-HaRas-induced SRE-mediated gene expression. These data suggest that intracellular signals activated by v-Src and mediated by HaRas are differentially regulated by PP2A.

3T3 Cells↗