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PubMed2001

DNA vaccination against v-src oncogene-induced tumours in congenic chickens.

DNA vaccination is particularly efficient for induction of cytotoxic T-lymphocyte (CTL) response. In our experiments, we used MHC(B) congenic chicken lines CB and CC (regressors and progressors of v-src-induced tumours, respectively) and a mutated, non-oncogenic v-src gene construct as the DNA vaccine. A high degree of vaccine protection against oncogenic v-src challenge was achieved in the CB line chickens. CTL response was demonstrated in vitro and by adoptive transfer of immune cells to the syngeneic host and to the CC line chickens rendered tolerant to CB cells. In the CC line chickens we observed tumour growth retardation after a low-dose DNA vaccination administered to immature recipients while higher amounts of DNA vaccine in immunocompetent chickens exerted an enhancing effect.

Adoptive Transfer↗
PubMed2006

Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway.

Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells.

Animals↗
PubMed1992

Multiple src-related kinase genes, srk1-4, in the fresh water sponge Spongilla lacustris.

In one of the simplest metazoan organisms, the sponge Spongilla lacustris, at least four different src-related kinase genes (srk1-4) are expressed, all of which show a high degree of similarity to the c-src genes of vertebrates. Whereas srk2 and srk3 are clearly unrelated at the nucleic acid level, srk1 and srk4 share identical sequences in the 5' parts of their cDNAs. The cloning of several primer extension clones and genomic polymerase chain reaction experiments confirmed the hypothesis of an alternative splicing of tandemly arranged carboxy-terminal parts of srk1 and srk4. The genomic sequence encoding both proteins was found to be interrupted at the splice point by an intron which is located in the same position as one of the introns in the chicken src gene, which is the only gene conserved in invertebrates and vertebrates. All four srk genes are expressed in adult sponges as mRNA transcripts of about 2.2 kb. Tyrosine kinase activity of a src-related kinase could be detected in adult sponges but not in their resting form (gemmulae), and may reflect the activity of the srk protein products. Spongilla lacustris is the simplest organism from which a protein tyrosine kinase gene has been isolated. The presence of at least four such genes in the evolutionary ancient and primitive phylum Porifera suggests that tyrosine kinase genes arose concomitantly with or shortly after the appearance of multicellular organisms and that their activity may be involved in aggregation and cell-cell recognition.

Amino Acid Sequence↗
PubMed2000

Selected glimpses into the activation and function of Src kinase.

Since the discovery of the v-src and c-src genes and their products, much progress has been made in the elucidation of the structure, regulation, localization, and function of the Src protein. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, differentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. Src associates with cellular membranes, in particular the plasma membrane, and endosomal membranes. Studies indicate that the different subcellular localizations of Src could be important for the regulation of specific cellular processes such as mitogenesis, cytoskeletal organization, and/or membrane trafficking. This review will discuss the history behind the discovery and initial characterization of Src and the regulatory mechanisms of Src activation, in particular, regulation by modification of the carboxy-terminal regulatory tyrosine by phosphatases and kinases. Its focus will then turn to the different subcellular localizations of Src and the possible roles of nuclear and perinuclear targets of Src. Finally, a brief section will review some of our present knowledge regarding Src involvement in human cancers.

Animals↗
PubMed1989

Function, location, and regulation of the src protein-tyrosine kinase.

The physiological roles, precise locations, and relevant targets of the 60 kD protein-tyrosine kinase encoded by viral and cellular src genes p60src are not known, despite intensive study. We describe recent work that bears upon these unresolved problems: (i) p60c-src is phosphorylated during mitosis on threonine and serine residues by the protein kinase encoded by the mammalian homologue of cdc2, suggesting that c-src may contribute to the phenotype of mitotic cells; (ii) multiple regions in the amino-terminal portion of p60src are required for its proper intracellular localization--a short signal for myristylation and signals for association with cytoplasmic granules and with perinuclear and plasma membranes; and (iii) regions (called SH3 and SH2) upstream of the kinase domain modulate the behavior of p60src in complex ways, with some mutations in SH2 rendering p60 host-dependent for transformation. The latter mutants may prove to be powerful tools for identifying proteins that modify or serve as targets for src-encoded protein-tyrosine kinases.

Amino Acid Sequence↗
PubMed1988

Genetic regulation of cell-to-cell communication.

Overexpression of the cellular src gene in NIH-3T3 cells causes reduction of cell-to-cell transmission of molecules in the 400-700 dalton range. This down-regulation of gap junctional communication correlates with the activity of the gene product, the protein tyrosine kinase pp60c-src. The down-regulation is enhanced by point mutation of Tyr527 (a site phosphorylated in pp60c-src and which inhibits kinase activity) or by substitution of the viral- for the cellular-src carboxyl terminal coding region. Mutation of Tyr416 (a site phosphorylated upon Tyr527 mutation) suppresses both the down-regulation by Tyr527 mutation and that by gene overexpression. The regulation of communication by src may be important in the control of embryonic development and cellular growth.

Cell Communication↗
PubMed2003

The 3' untranslated region of the chicken c-src protooncogene modulates gene expression.

Tight regulation of the Src tyrosine kinase activity is essential for a variety of cellular processes, namely transitions of the cell cycle. The peaks of Src activity are dependent on its posttranslational modifications as well as on the regulation of gene expression. The 3'UTRs of mRNAs are often crucial for rapid changes of the protein level. The chicken c-src 3'UTR effects on gene expression have been explored. The c-src 3'UTR decreased the in vivo tumorigenic potential of the src-activated mutants in chickens. This corresponds with the finding that the c-src 3'UTR reduced the Src protein and src mRNA levels and luciferase activity in vitro. Our results suggest that the chicken c-src 3'UTR plays a role in the negative control of gene expression, either transcriptionally or posttranscriptionally.

3' Untranslated Regions↗
PubMed2005

Novel insights into c-Src.

Since identifying a transmissible agent responsible for tumorigenesis in chickens, the v-Src oncogene, significant progress has been made in determining the functions of its cellular homologue. c-Src is the product of the SRC gene and has been found both over-expressed and highly activated in a number of human cancers. In fact the relationship between c-Src activation and cancer progression is significant. Furthermore c-Src may play a role in the acquisition of the invasive and metastatic phenotype. In this review we will summarize some of the latest evidence for the role of c-Src in tumorigenesis and particularly in human tumor progression. In this review, specifically, we will address growth signals, adhesion, migration, invasion, angiogenesis and functional genomics.

Animals↗
PubMed1991

Expression of v-src in embryonic neural retina alters cell adhesion, inhibits histogenesis, and prevents induction of glutamine synthetase.

Using Rous sarcoma virus as the vector, v-src or c-src genes were introduced into 6-day chicken embryo retina tissue in organ culture and their effects on retina development were investigated. Overexpression of c-src in many of the cells had no noticeable effect on retina development. In contrast, infection with v-src resulted in abnormal histogenesis and inhibition of differentiation. Although only a portion of the cells in infected tissue expressed the oncogene and displayed the transformation phenotype, the other cells were also hindered from becoming normally positioned and organized. Therefore, presence of oncogene-transformed cells within the tissue hindered organization and development of adjacent nontransformed cells. Failure of normal cell relationships impeded induction by cortisol of glutamine synthetase in Muller glia, which requires contact associations of the glia cells with neurons. The transformed cells tended to assemble into chaotic clusters, suggesting that their adhesiveness and contact affinities had become altered. This was confirmed by aggregation experiments with dissociated cells which showed that adhesiveness of transformed cells was greatly reduced and that they had lost the ability to cohere with nontransformed cells. In binary mixtures of transformed and nontransformed cells, the two sorted out into separate aggregates. Transformed cells formed loose clusters devoid of tissue architecture; aggregates of nontransformed cells became organized into retinotypic structures, and glutamine synthetase was inducible. Our findings suggest that the mechanisms of cell adhesion and cell affinities are a key target of v-src activity in infected cells and that modification of the cell surface may be a leading factor in other cellular changes characteristic of the v-src transformation phenotype.

Animals↗
PubMed1993

Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts.

Osteopetrosis is a bone modeling disorder resulting in excessive accumulation of bone matrix due to defective function of osteoclasts, the cells that resorb bone. Mice carrying a targeted disruption of the gene Src that encodes pp60c-src (Src), a nonreceptor protein tyrosine kinase, develop this phenotype but do not exhibit other overt defects despite the fact that the kinase is normally present in a broad variety of cell types. Because Src is expressed in osteoblasts as well as in osteoclasts and both are required for normal bone resorption, the basic defect could occur in either cell type. In this study we have used in vitro approaches and fetal liver transplantation into irradiated Src- recipients to demonstrate that the inherent defect is with osteoclasts and autonomous of the bone marrow microenvironment. This result (i) identifies a cell type in which Src function is essential and cannot be replaced by other related kinases and (ii) should allow the isolation of a substrate that is specific to Src.

Animals↗
PubMed1980

The origin and structure of endogenous retroviral DNA.

DNA related to the genomes of avian leukosis viruses (ALV) and mouse mammary tumor viruses (MMTV) is widely distributed among normal chickens and mice. We have used restriction mapping techniques to compare individuals from inbred and outbred populations with respect to genetically-transmitted proviral DNA, in efforts to understand its origins and functions. We have found that outbred animals have variable numbers of ALV and MMTV proviruses located at various sites in their host genomes, with some animals apparently free of such endogenous proviruses. Inbred or partially inbred animals have very similar or identical patterns, suggesting that proviruses behave as stable genetic elements once introduced into the germ line. Moreover, several cellular genes, including the homologous of the src gene of avian sarcoma virus, are invariant, or nearly so, in similar tests of these animals. We conclude that the proviruses under study have been introduced into the germ lines of chickens and mice long after speciation, that they are still segregating among contemporary animals, and that they are unlikely to provide essential functions to their hosts.

Animals↗
PubMed1993

Expression of a novel form of Tec kinase in hematopoietic cells and mapping of the gene to chromosome 5 near Kit.

The Tec kinase was initially identified as a novel cytoplasmic protein tyrosine kinase that is preferentially expressed in the liver and is highly homologous to the Drosophila Dsrc28C src-related tyrosine kinase. In screening of interleukin 3 (IL-3)-dependent myeloid leukemia cells for protein tyrosine kinases, we observed that all cell lines examined expressed high levels of Tec transcripts. However, characterization of Tec cDNAs indicated that they differed significantly from the published sequence. Most strikingly, an insertion of 41 bp in the 5' region affects the initiation codon and results in replacing the published 13 amino acid amino-terminal sequences with 94 amino acids. Using polymerase chain reaction (PCR) analysis, only the form containing the insertion was detected in hematopoietic cells. In addition, we found an in-frame insertion of 66 bp that introduces an additional 22 amino acids into the SH3 domain. This insertion restores conserved SH3 sequences that are found in the src gene family and in the Dsrc28C gene. By PCR analysis, approximately equal levels of Tec transcripts containing the intact SH3 domain and containing the 22 amino acid deletion were found in hematopoietic cells. Lastly, by interspecies backcross analysis, we show that the Tec gene is tightly linked to the c-Kit gene on mouse chromosome 5.

Amino Acid Sequence↗
PubMed1984

pp60c-src is developmentally regulated in the neural retina.

We have localized normal cellular pp60c-src in the developing chick neural retina by immunocytochemical staining using antisera raised against bacterially expressed pp60v-src, the src gene product of Rous sarcoma virus. pp60c-src was expressed in developing retinal neurons at the onset of differentiation. Expression of pp60c-src persisted in mature neuronal cells that were postmitotic, fully differentiated, and functional. pp60c-src immunoreactivity was localized within processes and cell bodies of ganglion neurons, processes of rods and cones, and in some but not all neurons of the inner nuclear layer. Protein kinase assays and Western transfer analyses identified the immunoreactive protein as pp60c-src, and confirmed that its expression occurs at the time the first neuronal cells in the retina differentiate. We conclude from these studies that pp60c-src is the product of a developmentally regulated gene that is more important in neuronal differentiation or function than cell proliferation.

Animals↗
PubMed1984

Complete env gene deletions of three replication-defective strains of Rous sarcoma virus and a model for the origin of their genetic structures.

Replication-defective deletion mutants of Rous sarcoma virus (RSV) have been described which transform cells in culture and elaborate envelope (-) defective particles. The env deletions of two clonal variants of the Bryan strain of RSV, RSV(-)3, and RSV(-)16, and of a replication-defective variant of Schmidt-Ruppin RSV (SRN8) were analyzed by fingerprinting oligonucleotides hybridized by a molecularly cloned env DNA probe that spans from near the 3' end of pol to the 3' end of env. It was observed that all three replication-defective RSV strains are essentially complete env deletions but retain the 3' end of pol. Based on a common pol-src junction oligonucleotide that may reflect a homologous sequence repeated at both ends of env in nondefective RSV, the env deletions of RSV(-)3 and 16 appear to be isogenic. The original deletion may have involved recombination between these sequences. The absence of this oligonucleotide in SRN8 indicates that the env deletion of SRN8 has different borders and represents an independent env deletion of nondefective RSV. All three defective RSVs have the genetic structure gag-pol-src. This genetic structure is consistent with the need for a complete gag to make a particle and with the assumption that an independent src gene rather than a gag- or gag-pol-src hybrid gene functions in transformation. It is suggested that a complete pol is not necessary for, but may assist, virus particle formation.

Avian Sarcoma Viruses↗
PubMed1999

Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts.

BACKGROUND: Fyn and c-Src are two of the most widely expressed Src-family kinases. Both are strongly implicated in the control of cytoskeletal organization and in the generation of integrin-dependent signalling responses in fibroblasts. These proteins are representative of a large family of tyrosine kinases, the activity of which is tightly controlled by inhibitory phosphorylation of a carboxyterminal tyrosine residue (Tyr527 in chicken c-Src); this phosphorylation induces the kinases to form an inactive conformation. Whereas the identity of such inhibitory Tyr527 kinases has been well established, no corresponding phosphatases have been identified that, under physiological conditions, function as positive regulators of c-Src and Fyn in fibroblasts. RESULTS: Receptor protein tyrosine phosphatase alpha (RPTPalpha) was inactivated by homologous recombination. Fibroblasts derived from these RPTPalpha-/- mice had impaired tyrosine kinase activity of both c-Src and Fyn, and this was accompanied by a concomitant increase in c-Src Tyr527 phosphorylation. RPTPalpha-/- fibroblasts also showed a reduction in the rate of spreading on fibronectin substrates, a trait that is a phenocopy of the effect of inactivation of the c-src gene. In response to adhesion on a fibronectin substrate, RPTPalpha-/- fibroblasts also exhibited characteristic deficiencies in integrin-mediated signalling responses, such as decreased tyrosine phosphorylation of the c-Src substrates Fak and p 130(cas), and reduced activation of extracellular signal regulated (Erk) MAP kinases. CONCLUSIONS: These observations demonstrate that RPTPalpha functions as a physiological upstream activator of Src-family kinases in fibroblasts and establish this tyrosine phosphatase as a newly identified regulator of integrin signalling.

Animals↗
PubMed1994

Evidence that c-src is involved in the process of osteoclastic bone resorption.

Transgenic mice lacking a functional c-src gene have osteopetrosis, a bone disorder characterized by defective osteoclast function. We have investigated the effects of selective protein tyrosine kinase inhibitors that are known to inhibit c-src, on osteoclast activity in the bone slice assay. Geldanamycin, herbimycin A and monorden (0.001-10 microM) all dose-dependently inhibited bone resorption with IC50 values of 8, 70 and 86 nM, respectively. At concentrations of 0.001-1 microM, the compounds were not cytotoxic as judged by osteoclast morphology and survival on bone slices. In order to determine whether c-src plays a role in signal transduction associated with osteoclast activation prior to bone resorption commencing, or in the resorptive process itself, we performed kinetic experiments using human calcitonin as a positive control. Calcitonin inhibited all bone resorption subsequent to its addition at t = 0, 3 or 6 hr (100%, approximately 90% and approximately 50% inhibition, respectively), after the start of the 24 hr bone slice assay. Similar results were obtained with herbimycin A and geldanamycin (1 microM) added at t = 0, 3 or 6 hr, and with monorden (1 microM) added at t = 0 and 6 hr. These results indicate that c-src plays a crucial and continuous role in the process of osteoclastic bone resorption, most likely related to the translocation and/or fusion of exocytic vesicles to the ruffled border membrane.

Animals↗
PubMed1982

Cellular sequences related to three new onc genes of avian sarcoma virus (fps, yes, and ros) and their expression in normal and transformed cells.

Two onc genes of avian sarcoma viruses unrelated to the src gene have recently been identified: fps of Fujinami sarcoma virus/PRCII/UR1 and yes of Y73/Esh sarcoma virus. In the first part of this study we demonstrated that UR2, the most recently isolated avian sarcoma virus, contains in its genome a unique sequence, ros, nonhomologous to src, fps, and yes sequences or to transforming genes of avian acute leukemia viruses. Using cDNAs specific to the inserts of avian sarcoma virus genomes, we examined the existence and the transcription of cellular nucleotide sequences related to the three new onc genes of avian sarcoma virus (fps, yes and ros) in various cells. The progenitor cellular sequences for these onc genes (c-onc) were present in uninfected chicken DNA in one or few copies per haploid genome. These c-onc sequences were detectable in cellular DNA of a wide variety of vertebrates, and the homology between viral and cellular onc was inversely related to the phylogenetic distance of animal species. The pattern of expression of these c-onc genes in different tissues of chickens was found to be unique to each gene. The expression of c-fps and c-ros genes was generally repressed in many tissues, but c-fps was expressed at higher levels in bone marrow (2.5 copies per cell) and lung (1.1 copies per cell), whereas c-ros was mainly transcribed in kidney (2.5 copies per cell). On the other hand, c-yes transcripts were easily detectable in all tissues analyzed and were found at high levels in kidney (26 copies per cell). These c-onc expressions were unaffected by infection with avian sarcoma viruses that contained other onc genes. In a few cultures of chicken and quail transformed cells derived from tumors induced by chemical carcinogens, we found that the levels of transcription of the four c-onc genes remained unaltered, compared with that in normal tissues.

Alpharetrovirus↗
PubMed1994

Transformation by v-src causes transient induction followed by repression of mouse thrombospondin-1.

Thrombospondin-1 (TSP-1) is an extracellular glycoprotein that plays a role in neoplasia, cell growth, and differentiation. We have examined the regulation of TSP-1 mRNA in cells expressing the v-src oncogene. Rat1 fibroblasts constitutively transformed by v-src expressed TSP-1 mRNA at levels that were 10- to 50-fold lower than those observed in parental, vector-transfected control cells. To analyze the kinetics of this effect, we used a line of BALB/c 3T3 fibroblasts containing a thermolabile v-src gene. Prolonged culture of these cells at the permissive temperature also resulted in down-regulation of TSP-1 mRNA. However, at early time points after temperature shift of growth-arrested cells, we observed a 3- to 15-fold increase in TSP-1 mRNA. This induction was abolished by the tyrosine kinase inhibitor, herbimycin-A, but not by the protein synthesis inhibitor, cycloheximide. The induction of TSP-1 by v-src occurred at a transcriptional level, as determined by nuclear run-on assays. Furthermore, the effect was mediated in part by a short region of the TSP-1 promoter which contains only 41 base pairs of 5' flanking DNA and 48 base pairs of the first exon. We conclude that, while overexpression of v-src results in brief transcriptional induction of TSP-1, the ultimate result of v-src transformation, at least in rodent fibroblasts, is repression of TSP-1 gene expression.

Animals↗