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PubMed1991

Transcription of muscle-specific genes is repressed by reactivation of pp60v-src in postmitotic quail myotubes.

Quail myogenic cells infected with temperature sensitive (ts) mutants of Rous sarcoma virus (RSV) exhibit a temperature-dependent transformation and block of differentiation. When the cells are allowed to differentiate at the restrictive temperature (41 degrees C) and then shifted back to the permissive temperature (35 degrees C), a sharp reduction in the accumulation of muscle-specific mRNAs is observed, following reactivation of the transforming protein pp60v-src. A kinetic analysis of this down-regulation reveals that the reduction in the accumulation of muscle-specific transcripts occurs fairly rapidly within 6 to 20 h after the shift back, depending on the mRNA analyzed. Studies on transcription of endogenous muscle-specific genes and a transfected chloramphenicol acetyltransferase reporter gene under the control of muscle-specific promoters, at the different temperatures, suggest that the oncogene exerts its control mainly at the transcriptional level. On the contrary, transcription of the CMD1 gene, the avian homolog of the mouse muscle regulatory MyoD gene, is not significantly affected by the oncogene both in proliferating myoblasts and in myotubes shifted back to 35 degrees C. These findings are consistent with the conclusion that v-src blocks myogenesis by controlling transcription of muscle-specific genes independently of cell proliferation. Furthermore, they suggest the existence of an alternative pathway, not requiring the silencing of CMD1 transcription, through which the oncogene exerts its effect.

Actins↗
PubMed1991

Expression of lineage-restricted protein tyrosine kinase genes in human natural killer cells.

The hematopoietic lineage derivation, recognition structures and associated signal transduction pathways of CD3- natural killer (NK) cells have not been identified. Protein tyrosine kinases (PTK) structurally related to the product of the c-src protooncogene are differentially expressed in distinct hematopoietic differentiation lineages and may participate in specific signal transduction pathways. The present study was aimed at characterizing the expression of src-related PTK genes in normal human NK cells and in cells from patients with CD3- granular lymphocyte proliferative disease. CD3- normal NK cells had high levels of transcripts of the lck gene, which is highly expressed in T cells. CD8+ and CD8- NK cells expressed similarly high levels of lck mRNA. In contrast, NK cells expressed very low levels (25-80 times less than monocytes) of mRNA encoding the myelomonocytic PTK hck. NK cells also expressed fyn transcripts (p59fyn reportedly associates with the T cell receptor in T cells) and fgr transcripts, the latter observation confirming a previous report. The pattern of expression of the lineage-restricted PTKs lck and hck in NK cells is consistent with the hypothesis of an ontogenic relationship of this population with the lymphocytic rather than myelocytic differentiation pathway. PTK expressed in NK cells may participate in signal transduction pathways in this cell population.

Antigens, CD↗
PubMed1994

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer.

Adenoma↗
PubMed1992

The p60c-src family of protein-tyrosine kinases: structure, regulation, and function.

In 1911, Peyton Rous reported that a fibrosarcoma could be transmitted between chickens in a cell-free extract of the tumor. The transmissible agent, Rous sarcoma virus (RSV), transforms cells by virtue of the presence within its genome of a viral oncogene, v-src, which is derived from a normal cellular gene that has been picked up, or transduced, by the virus. This cellular proto-oncogene, c-src, encodes a protein, p60c-src, which has the ability to phosphorylate proteins on tyrosine residues. Studies of RSV were thus directly responsible for the discovery of cellular proto-oncogenes and of protein-tyrosine kinases, discoveries which have been fundamental in shaping our ideas about cellular growth control. In spite of this, the normal biological role of p60c-src is still unclear and it remains impossible to provide a full answer to the question of how RSV causes tumors. It is clear, however, that c-src is the prototype of a family of at least 8 closely related genes encoding protein tyrosine kinases, the other family members being blk, c-fgr, fyn, hck, lck, lyn, and c-yes. The purpose of this review is to outline our current knowledge of the structure, expression pattern, and function of each of the members of the c-src gene family and to describe recent data which begins to explain how these proteins interact with other cellular proteins to control cell behavior. The evidence for involvement of these proteins in oncogenesis is also discussed.

Amino Acid Sequence↗
PubMed1983

Tumor induction by direct injection of cloned v-src DNA into chickens.

The in vitro transforming potential of Rous sarcoma viruses has been shown to reside in a gene segment, v-src. To provide direct proof that the isolated v-src sequence contains all the information necessary for sarcoma induction in vivo, we have injected subgenomic and genomic cloned DNA carrying v-src directly into chickens. We report that v-src, without the complements of other viral genes, can effectively induce sarcomas in the host within weeks after injection. The sarcoma tumors generated by subgenomic v-src DNA are of mono- or oligoclonal origin. They have acquired v-src sequences in the genome and expressed high levels of src messages. Intact long terminal repeats do not seem to be essential in the tumorigenic process.

Animals↗
PubMed2003

Inhibition of c-src transcription by mithramycin: structure-activity relationships of biosynthetically produced mithramycin analogues using the c-src promoter as target.

The aureolic acid antitumor antibiotic mithramycin (MTM) inhibits both cancer growth and bone resorption by cross-linking GC-rich DNA, thus blocking binding of Sp-family transcription factors to gene regulatory elements. Transcription of c-src, a gene implicated in many human cancers and required for osteoclast-dependent bone resorption, is regulated by the binding of Sp factors to specific elements in its promoter. Therefore, this gene represents an important anticancer target and a potential lead target through which MTM displays its so far uncharacterized action against osteoclastic bone resorption. Here we demonstrate, using DNA binding studies, promoter reporter assays, and RT-PCR, that MTM inhibits Sp binding to the c-src promoter region, thereby decreasing its expression in human cancer cells. Furthermore, selected mithramycin analogues, namely, premithramycin B, mithramycin SK, 7-demethylmithramycin, 4E-ketomithramycin, and 4C-ketodemycarosylmithramycin, generated through combinatorial biosynthesis, were compared with MTM for their ability to block Sp binding to the c-src promoter. Although most of the tested compounds lost their ability to bind to the DNA, alteration of the MTM 3-pentyl side chain led to a compound (mithramycin SK) with the same DNA binding specificity but with lower binding affinity than MTM. While this compound was comparable to MTM in promoter reporter, gene expression, and anticancer assays, given its weaker interaction with the DNA, it may be much less toxic than MTM. The results presented here supplement recent findings and, moreover, allow new conclusions to be made regarding both the structure-activity relationships, particularly with respect to the alkyl side chains, and the mechanism of action of aureolic acid drugs.

Antibiotics, Antineoplastic↗
PubMed1999

Mouse steroid receptor coactivator-1 is not essential for peroxisome proliferator-activated receptor alpha-regulated gene expression.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors, and it is assumed that the biological effects of these receptors depend on interactions with recently identified coactivators, including steroid receptor coactivator-1 (SRC-1). We assessed the in vivo function of SRC-1 on the PPARalpha-regulated gene expression in liver by generating mice in which the SRC-1 gene was inactivated by gene targeting. The homozygous (SRC-1(-/-)) mice were viable and fertile and exhibited no detectable gross phenotypic defects. When challenged with a PPARalpha ligand, such as ciprofibrate or Wy-14,643, the SRC-1(-/-) mice displayed typical pleiotropic responses, including hepatomegaly, peroxisome proliferation in hepatocytes, and increased mRNA and protein levels of genes that are regulated by PPARalpha. These alterations were indistinguishable from those exhibited by SRC-1(+/+) wild-type mice fed either ciprofibrate- or Wy-14, 643-containing diets. These results indicate that SRC-1 is not essential for PPARalpha-mediated transcriptional activation in vivo and suggest redundancy in nuclear receptor coactivators.

Animals↗
PubMed1998

The many faces of Src: multiple functions of a prototypical tyrosine kinase.

c-src was first isolated as the normal cellular homologue of v-src, the transforming gene of Rous Sarcoma virus (Stehelin et al., 1976). As the first proto-oncogene described and one of the first molecules demonstrated to have tyrosine kinase activity, Src has provided a prototype for understanding signal transduction involving tyrosine phosphorylation. Comparison between c-src and activated or transforming mutants of Src including v-src, combined with recent data on the structure of Src family kinases has provided new insight into their regulation. In this review, I will discuss the function of the various domains of Src in light of these mutational and structural studies.

Animals↗
PubMed1997

EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.

The MLL gene, the closest human homologue to the Drosophila trithorax gene, undergoes chromosomal translocation with a large number of different partner genes in both acute lymphoid and acute myeloid leukemias. We have identified a new partner gene, EEN, fused to MLL in a case of acute myeloid leukemia. The gene is located on chromosome 19p13, where two other MLL partner genes, ENL and ELL/MEN have also been identified. The deduced protein of 368 aa contains a central alpha-helical region and a C-terminal Src homology 3 (SH3) domain most similar to the C-terminal SH3 domain found in the Grb2/Sem-5/Drk family of genes. Sequence analysis of the fusion MLL/EEN transcript in our patient reveals that exon 6 of MLL is fused to the N-terminal end of EEN, a fusion that would create a chimeric protein that includes the major functional domain of EEN. EEN is expressed in a variety of tissue types and encodes a protein of approximately 46 kDa. The EEN protein is the human homologue of a member of a recently described murine SH3 domain-containing protein family. It is also highly related to a putative gene identified in Caenorhabditis elegans, and a number of similar sequences are present in the EST databases of several species.

Amino Acid Sequence↗
PubMed1996

Transcriptional down regulation of the nov proto-oncogene in fibroblasts transformed by p60v-src.

We have sought to identify genes whose expression is altered as a consequence of transformation by p60v-src. Using the mRNA differential display method, we have identified the nov proto-oncogene as one gene that is down regulated in chicken embryo fibroblasts (CEFs) transformed by p60v-src. nov transcripts were also found to be present at only very low levels in proliferating CEFs in comparison with quiescent CEFs. Serum stimulation of quiescent CEFs also resulted in a decline in the steady-state level of nov transcripts. Taken together, these findings suggest that the nov gene is expressed only in quiescent fibroblasts and that its down regulation may contribute to cellular transformation by the v-src oncogene. Down regulation of the nov gene appears to occur at both the transcriptional and posttranscriptional levels. Results obtained from experiments with a protein kinase inhibitor suggest that protein kinase C may be a key downstream effector in mediating the down regulation of nov transcripts in response to activation of p60src or serum stimulation. In addition, we found that transcription of an unknown gene is required for the decline in the steady-state level of nov transcripts in response to serum stimulation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2004

Abrogation of autoimmune disease in Lyn-deficient mice by the deletion of IL-5 receptor alpha chain gene.

Lyn, the src-family protein tyrosine kinase, plays a crucial role in the regulation of B cell antigen receptor (BCR)- and IL-5-receptor (IL-5R)-mediated signaling. Lyn-deficient mice have been reported to exhibit an increase in B-1 cell numbers, splenomegaly and accumulation of lymphoblast-like cells in the spleen with age, resulting in hyperimmunoglobulinemia and glomerulonephritis caused by the deposition of autoantibody complexes. To elucidate the role of IL-5 in B-1 cell activation, autoantibody production and autoimmune diseases, Lyn-deficient mice were crossed with IL-5Ralpha chain (IL-5Ralpha)-deficient mice and generated Lyn- and IL-5Ralpha-deficient (DKO) mice. In contrast to Lyn-deficient mice, DKO mice showed significantly reduced splenomegaly and lymphoadenopathy and reduced B-1 cell number in the peritoneal cavity. DKO mice also secreted low levels of IgM and IgG autoantibodies. Biochemical and histological analyses revealed that DKO mice showed milder pathogenesis of autoimmune-like disorders than Lyn-deficient mice. These results suggest involvement of IL-5 in enhanced B-1 cell activation, autoantibody production, and development of autoimmune disease in Lyn-deficient mice.

Animals↗
PubMed1994

Specific recognition of the blk promoter by the B-lymphoid transcription factor B-cell-specific activator protein.

Several genes of the src family encode protein-tyrosine kinases that associate with the B-cell antigen receptor complex and are activated upon receptor cross-linking, including blk, lyn, and fyn. The blk gene is the only member of this family whose expression is restricted to B-lymphoid cells. In the B lineage, blk is developmentally regulated: blk transcripts are first detected in pro-B-cells and persist until the differentiation of mature B-cells to plasma cells. We have found that the blk promoter is a target for a specific DNA-binding protein whose activity in B-lymphoid cell lines is positively correlated with blk expression. By three criteria, we have identified this DNA-binding protein as the transcription factor B-cell-specific activator protein (BSAP): 1) oligonucleotides containing known BSAP recognition sites were found to compete specifically with blk for binding to the protein detected in B-lymphoid extracts; 2) authentic BSAP was shown to bind the same site within the blk promoter as the protein identified in B-lymphoid extracts; and 3) the specific DNA-protein complex formed in B-lymphoid extracts was shown to react with an anti-BSAP antiserum. BSAP has been implicated previously in the transcriptional regulation of CD19, whose pattern of expression in B-cell development coincides with that of blk. These observations, and the correlation between expression of BSAP and expression of blk, suggest that BSAP is a positive regulator of blk transcription.

B-Lymphocytes↗
PubMed1992

Infection of terminally differentiated myotubes with Rous sarcoma virus: reduced synthesis of env and v-src proteins.

We studied Rous sarcoma virus (RSV) protein synthesis in RSV-infected, terminally differentiated chicken myotubes ('late-infected' myotubes), in which no viral DNA integration takes place but all three viral mRNAs (38S, 28S and 21S) are transcribed normally. With the use of specific anti-RSV protein antisera, we found that only the viral gag and pol proteins were synthesized at levels similar to those synthesized in RSV-transformed fibroblasts; the synthesis of env and v-src proteins was significantly reduced in these infected myotubes. We concluded that the viral RNA transcribed from the unintegrated RSV DNA was functional but that genes at the 3' end of the RSV genome were translated at a lower level. By contrast, when mononucleated replicating chicken myoblasts were infected with a mutant (tsNY68) carrying a temperature-sensitive v-src gene and maintained at the non-permissive temperature for this gene, they developed into myotubes with viral DNA integrated in their chromosomal DNA. These 'early-infected' myotubes expressed all four viral genes (gag, pol, env and v-src) at a level similar to that in infected fibroblasts. This result ruled out the possible presence of specific factor(s) in myotubes that preferentially inhibit the 3' genes of RSV, and suggested other translational control(s) of viral gene expression in late-infected myotubes.

Animals↗
PubMed1985

Members of the src and ras oncogene families supplant the epidermal growth factor requirement of BALB/MK-2 keratinocytes and induce distinct alterations in their terminal differentiation program.

BALB-/MK-2 mouse epidermal keratinocytes required epidermal growth factor for proliferation and terminally differentiated in response to high Ca2+ concentration. Infection with retroviruses containing transforming genes of the src and ras oncogene families led to rapid loss of epidermal growth factor dependence, in some cases, accompanied by alterations in cellular morphology. The virus-altered cells continued to proliferate in the presence of high levels of extracellular calcium but exhibited alterations in normal keratinocyte terminal differentiation that appear to be specific to the particular oncogene. These alterations bore similarities to abnormalities in differentiation observed in naturally occurring squamous epithelial malignancies.

Animals↗
PubMed1983

Loss of proviral sequences in RSV-transformed mouse tumour cells accompanied by the formation of double-minute chromatin bodies.

The RVA2 cell line, derived originally from a tumour induced by the Schmidt-Ruppin strain of RSV and passaged repeatedly in vivo and in vitro, was studied. This cell line was originally virogenic and the virus was rescuable with high efficiency from it. When rechecked after prolonged passage history, the efficiency of virus rescue was found to drop to very low levels and from one monocellular clone derived from such cell population no virus was rescued at all. After further 14 in vivo passages of RVA2 cells, no transforming virus rescue was obtained, even in the presence of a helper virus. Nor were the U5 sequences of LTR found in these cells. Karyologic analysis revealed the presence of double-minute chromatin bodies in the RVA2 cell population studied. The frequency of mitoses containing DMs doubled after 14 in vivo passages. The possibility is discussed that DMs as the site of gene amplification also contain amplified cellular oncogenes which might take over direction of the malignant state of the cell in which the original transforming viral gene (v-src) is no longer active or is lost.

Animals↗
PubMed2007

The 1alpha,25-dihydroxy Vitamin D3 receptor preferentially recruits the coactivator SRC-1 during up-regulation of the osteocalcin gene.

Binding of 1alpha,25-dihydroxy Vitamin D3 to the C-terminal domain (LBD) of its receptor (VDR), induces a conformational change that enables interaction of VDR with transcriptional coactivators such as the members of the p160/SRC family or the DRIP (Vitamin D interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. Recent reports indicate that nuclear receptors, including VDR, interact with p160/SRC members and the DRIP/Mediator complex in a sequential, cyclical, and mutually exclusive manner when bound to a target promoter, exhibiting also a high exchange rate. Here, we present an overview of how these coactivators are recruited to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1alpha,25-dihydroxy Vitamin D3. We find that in intact osteoblastic cells VDR and SRC-1 rapidly bind to the OC promoter in response to the ligand. This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter. In contrast, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter after several hours of incubation with 1alpha,25-dihydroxy Vitamin D3. Together, our results indicate that VDR preferentially recruits SRC-1 to enhance basal bone-specific OC gene transcription. We propose a model where specific protein-DNA and protein-protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the VDR-SRC-1 complex.

Animals↗
PubMed1992

Evidence that Ha-Ras mediates two distinguishable intracellular signals activated by v-Src.

v-Src activates promoters under the control of 12-O-tetradecanoylphorbol-13-acetate (TPA) response elements (TREs) and serum response elements (SREs) via two distinguishable intracellular signaling mechanisms. The induction of TRE- and SRE-mediated gene expression by v-Src could be distinguished by a differential sensitivity to depleting cells of protein kinase C (PKC) and to a dominant negative Raf-1 mutant. Thus, PKC depletion and the dominant negative Raf-1 mutant were able to distinguish two intracellular signaling mechanisms activated by v-Src. Both of these v-Src-induced intracellular signals were sensitive to a dominant negative mutant of Ha-Ras. These data suggest that Ha-Ras functions to coordinately regulate multiple intracellular signaling mechanisms activated by v-Src.

3T3 Cells↗
PubMed1985

Analysis of a tyrosine-specific protein kinase activity associated with the retroviral erbB oncogene product.

The transforming protein erbB of avian erythroblastosis virus (AEV) has considerable sequence homology with the epidermal growth factor (EGF) and appears to represent a truncated form of this receptor. The sequence of the erbB gene is furthermore related to that of other viral transforming genes such as src, fps, yes or abl. The transforming proteins of these src-related oncogenes as well as receptors for EGF, platelet-derived growth factor (PDGF), and insulin are associated with tyrosine-specific protein kinases. It has been difficult to demonstrate this activity for the erbB protein. To analyze the erbB gene product, we prepared polyclonal antibodies against a bacterially expressed erbB DNA restriction fragment (BamHI/BamHI). The antiserum is shown to immunoprecipitate the erbB protein from AEV-transformed chicken fibroblasts and also recognizes the EGF receptor protein. Both proteins become phosphorylated in vitro on tyrosine residues upon the addition of [gamma-32P]ATP. The protein kinase activity is low compared to other oncogene-specific kinases. This is not due to kinase blocking by the serum, because erbB carboxyterminal synthetic peptide antibodies give rise to low levels of protein kinase activity as well indicating that this may be a characteristic property of erbB in vitro.

Alpharetrovirus↗