Biomedical subjects

R A Van Etten

Publications and source records attributed to R A Van Etten.

At least 19 recordsLinked to original sources

PubMed2003

Childhood leukemia: electric and magnetic fields as possible risk factors.

Numerous epidemiologic studies have reported associations between measures of power-line electric or magnetic fields (EMFs) and childhood leukemia. The basis for such associations remains unexplained. In children, acute lymphoblastic leukemia represents approximately three-quarters of all U.S. leukemia types. Some risk factors for childhood leukemia have been established, and others are suspected. Pathogenesis, as investigated in animal models, is consistent with the multistep model of acute leukemia development. Studies of carcinogenicity in animals, however, are overwhelmingly negative and do not support the hypothesis that EMF exposure is a significant risk factor for hematopoietic neoplasia. We may fail to observe effects from EMFs because, from a mechanistic perspective, the effects of EMFs on biology are very weak. Cells and organs function despite many sources of chemical "noise" (e.g., stochastic, temperature, concentration, mechanical, and electrical noise), which exceed the induced EMF "signal" by a large factor. However, the inability to detect EMF effects in bioassay systems may be caused by the choice made for "EMF exposure." "Contact currents" or "contact voltages" have been proposed as a novel exposure metric, because their magnitude is related to measured power-line magnetic fields. A contact current occurs when a person touches two conductive surfaces at different voltages. Modeled analyses support contact currents as a plausible metric because of correlations with residential magnetic fields and opportunity for exposure. The possible role of contact currents as an explanatory variable in the reported associations between EMFs and childhood leukemia will need to be clarified by further measurements, biophysical analyses, bioassay studies, and epidemiology.

Animals↗

PubMed2001

Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling.

Growth factor receptor-binding protein-2 (Grb2) plays a key role in signal transduction initiated by Bcr/Abl oncoproteins and growth factors, functioning as an adaptor protein through its Src homology 2 and 3 (SH2 and SH3) domains. We found that Grb2 was tyrosine-phosphorylated in cells expressing BCR/ABL and in A431 cells stimulated with epidermal growth factor (EGF). Phosphorylation of Grb2 by Bcr/Abl or EGF receptor reduced its SH3-dependent binding to Sos in vivo, but not its SH2-dependent binding to Bcr/Abl. Tyr209 within the C-terminal SH3 domain of Grb2 was identified as one of the tyrosine phosphorylation sites, and phosphorylation of Tyr209 abolished the binding of the SH3 domain to a proline-rich Sos peptide in vitro. In vivo expression of a Grb2 mutant where Tyr209 was changed to phenylalanine enhanced BCR/ABL-induced ERK activation and fibroblast transformation, and potentiated and prolonged Grb2-mediated activation of Ras, mitogen-activated protein kinase and c-Jun N-terminal kinase in response to EGF stimulation. These results suggest that tyrosine phosphorylation of Grb2 is a novel mechanism of down-regulation of tyrosine kinase signaling.

3T3 Cells↗

PubMed2001

Mutational analysis of the regulatory function of the c-Abl Src homology 3 domain.

The catalytic activity of the c-Abl tyrosine kinase is tightly regulated by its Src homology 3 (SH3) domain through a complex mechanism that may involve intramolecular binding to Pro242 in the linker region between the SH2 and catalytic domains as well as interactions with a trans-inhibitor. We analysed the effect of mutation or replacement of SH3 on c-Abl tyrosine kinase activity and transformation. Random mutagenesis of SH3 identified several novel point mutations that dysregulated c-Abl kinase activity in vivo, but the RT loop was insensitive to mutational activation. Activating SH3 mutations abolished binding of proline-rich SH3 ligands in vitro, while mutations at Ser140 in the connector between the SH3 and SH2 domains activated Abl kinase activity in vivo and in vitro but did not impair SH3 ligand-binding. Abl was regulated efficiently when its SH3 domain was replaced with a heterologous SH3 from c-Src that binds a different spectrum of proline-rich ligands, but not by substitution of a modular WW domain with similar ligand-binding specificity. These results suggest that the SH3 domain regulates Abl principally by binding to the atypical intramolecular ligand Pro242 rather than a canonical PxxP ligand. Coordination between the SH3 and SH2 domains mediated by the connector region may be required for regulation of Abl even in the absence of SH2 ligand binding.

Amino Acid Sequence↗

PubMed2001

Activation of c-Abl kinase activity and transformation by a chemical inducer of dimerization.

c-Abl is a non-receptor tyrosine kinase that is activated in human leukemias by the fusion of Bcr or Tel sequences to the Abl NH(2) terminus. Although Bcr and Tel have little in common, both contain oligomerization domains. To determine whether oligomerization alone is sufficient to activate c-Abl, we have generated and characterized an Abl protein that can be activated selectively with the chemical inducer of dimerization, AP1510. Mutant Abl proteins with one (c4F1) or two (c4F2) copies of the AP1510 binding motif (FKBP) transformed NIH 3T3 cells in a ligand-dependent manner with the c4F2 protein 60-fold more potent than c4F1. Both chimeric proteins exhibited ligand-dependent dimerization in vivo, suggesting that the increased transformation efficiency of the c4F2 mutant reflects more effective dimerization rather than formation of higher order oligomers. In the absence of ligand, c4F2-expresssing fibroblasts morphologically reverted and arrested in G(1). In Ba/F3 cells, the c4F2 chimera exhibited ligand-dependent kinase activation, transformation to interleukin 3-independent growth, and relocalization of the fusion protein from nucleus to cytoplasm. These results demonstrate that dimerization alone is sufficient to activate the Abl kinase and provide a method to regulate conditionally c-Abl activity that will be useful for studying the normal physiological role of c-Abl and the mechanism of transformation and leukemogenesis.

3T3 Cells↗

PubMed2001

Induction of myeloproliferative disease in mice by tyrosine kinase fusion oncogenes does not require granulocyte-macrophage colony-stimulating factor or interleukin-3.

Tyrosine kinase fusion oncogenes that occur as a result of chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of autocrine and paracrine expression of hematopoietic cytokines in leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD) caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth factor beta receptor (PDGFbetaR), TEL/Janus kinase 2 (JAK2), and TEL/neurotrophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGFbetaR and TEL/JAK2. However, all of the fusions tested efficiently induced MPD in mice genetically deficient for both GM-CSF and IL-3, demonstrating that these cytokines are not necessary for the development of disease in this model system. Furthermore, in experiments using normal marrow transduced with TEL/PDGFbetaR retrovirus mixed with marrow transduced with an enhanced green fluorescent protein (EGFP) retrovirus, the MPD induced in these mice demonstrated minimal stimulation of normal myelopoiesis by the TEL/PDGFbetaR-expressing cells. In contrast, recipients of mixed GM-CSF-transduced and EGFP-transduced marrow exhibited significant paracrine expansion of EGFP-expressing cells. Collectively, these data demonstrate that, although cytokine levels are elevated in murine bone marrow transplant models of leukemia using tyrosine kinase fusion oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by any of the oncogenes tested.

Animals↗

PubMed2001

Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL.

Primitive hematopoietic progenitors from some patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) express aberrant transcripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti-IL-3 and anti-IL-3 receptor antibodies. Expression of the product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, and some leukemic mice have increased circulating IL-3, and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF). These observations raise the possibility of autocrine or paracrine cytokine production in the pathogenesis of human CML. Mice with homozygous inactivation of the Il-3 gene, the Gm-csf gene, or both, were used to test the requirement for these cytokines for induction of CML-like disease by BCR/ABL. Neither IL-3 nor GM-CSF was required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demonstrated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was Il-3(-/-) indicated that the increased IL-3 originated from the recipient, suggestive of a host reaction to the disease. These results demonstrate that IL-3 and GM-CSF are not required for BCR/ABL-induced CML-like leukemia in mice and suggest that autocrine production of IL-3 does not play a role in established chronic phase CML in humans.

Animals↗

PubMed2001

The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase.

The effect of mutations in the Src homology 2 (SH2) domain of the BCR/ABL oncogene on leukemogenesis was tested in a quantitative murine bone marrow transduction/transplantation assay that accurately models human Philadelphia-positive B-lymphoid leukemia and chronic myeloid leukemia (CML). The SH2 domain was not required for induction of B-lymphoid leukemia in mice by BCR/ABL. Under conditions where the p190 and p210 forms of BCR/ABL induce fatal CML-like myeloproliferative disease within 4 weeks, p210 SH2 mutants induced CML-like disease in some mice only after a significant delay, with other recipients succumbing to B-lymphoid leukemia instead. In contrast, p190 BCR/ABL SH2 point and deletion mutants rapidly induced CML-like disease. These results provide the first direct evidence of significant differences in cell signaling by the Bcr/Abl tyrosine kinase between these distinct leukemias. Contrary to previous observations, high levels of phosphatidylinositol 3-kinase (PI 3-kinase) activity in primary malignant lymphoblasts and myeloid cells from recipients of marrow transduced with the BCR/ABL SH2 mutants were found. Hence, the decreased induction of CML-like disease by the p210 BCR/ABL SH2 mutants is not due to impaired activation of PI 3-kinase.

Animals↗

PubMed2001

Models of chronic myeloid leukemia.

Models of chronic myeloid leukemia (CML) have proven invaluable for furthering our understanding of the molecular pathophysiology of this disease. Xenotransplantation of primary human CML cells into immunodeficient mice allows investigation into the nature of the most primitive repopulating cells in this leukemia, but the system is limited by variability and difficulty with experimental manipulation. Accordingly, a large effort has been invested in developing models of CML through expression of the BCR/ABL oncogene in the hematopoietic system of laboratory mice. Despite numerous attempts, an accurate transgenic mouse model of CML has not been produced, possibly because of the toxicity of BCR/ABL. Conditional transgenic mice are a promising new approach to this problem. A more successful strategy is retroviral transduction of BCR/ABL into mouse bone marrow in vitro, followed by transplantation into syngeneic or immunodeficient recipient mice. Recipients of marrow transduced with p210 BCR/ABL develop a fatal myeloproliferative illness that closely resembles human CML. This model is being used to define the signaling pathways required for leukemogenesis by BCR/ABL, and for developing new therapeutic approaches.

Animals↗

PubMed2001

Pathogenesis and treatment of Ph+ leukemia: recent insights from mouse models.

Several methods to model human Ph+ leukemia in laboratory mice are available, including propagation of BCR/ABL-expressing cells in mice, xenotransplantation of primary Ph+ leukemia cells into immunodeficient mice, BCR/ABL transgenic mice, and BCR/ABL retroviral bone marrow transduction and transplantation. Recent studies in these different model systems have yielded important advances in our knowledge of the pathogenesis and therapy of human chronic myeloid leukemia and Ph+ B-lymphoblastic leukemia, and are the subject of this review.

Animals↗

PubMed2000

c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines.

Using the specific Abl tyrosine kinase inhibitor STI 571, we purified unphosphorylated murine type IV c-Abl and measured the kinetic parameters of c-Abl tyrosine kinase activity in a solution with a peptide-based assay. Unphosphorylated c-Abl exhibited substantial peptide kinase activity with K(m) of 204 microm and V(max) of 33 pmol min(-1). Contrary to previous observations using immune complex kinase assays, we found that a transforming c-Abl mutant with a Src homology 3 domain point mutation (P131L) had significantly (about 6-fold) higher intrinsic kinase activity than wild-type c-Abl (K(m) = 91 microm, V(max) = 112 pmol min(-1)). Autophosphorylation stimulated the activity of wild-type c-Abl about 18-fold and c-Abl P131L about 3.6-fold, resulting in highly active kinases with similar catalytic rates. The autophosphorylation rate was dependent on Abl protein concentration consistent with an intermolecular reaction. A tyrosine to phenylalanine mutation (Y412F) at the c-Abl residue homologous to the c-Src catalytic domain autophosphorylation site impaired the activation of wild-type c-Abl by 90% but reduced activation of c-Abl P131L by only 45%. Mutation of a tyrosine (Tyr-245) in the linker region between the Src homology 2 and catalytic domains that is conserved among the Abl family inhibited the autophosphorylation-induced activation of wild-type c-Abl by 50%, whereas the c-Abl Y245F/Y412F double mutant was minimally activated by autophosphorylation. These results support a model where c-Abl is inhibited in part through an intramolecular Src homology 3-linker interaction and stimulated to full catalytic activity by sequential phosphorylation at Tyr-412 and Tyr-245.

Animals↗

PubMed2000

The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase.

The BCR/ABL oncogene results from a balanced translocation between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177. A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic cell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl-Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/transplantation model system. The Y177F mutation greatly attenuates the myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. These results suggest that direct binding of Grb2 is required for the efficient induction of CML-like myeloproliferative disease by oncogenic Abl proteins. (Blood. 2000;96:664-670)

3T3 Cells↗

PubMed2000

Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth.

Cyclin-dependent kinase 5 (Cdk5) is a small serine/threonine kinase that plays a pivotal role during development of the CNS. Cables, a novel protein, interacts with Cdk5 in brain lysates. Cables also binds to and is a substrate of the c-Abl tyrosine kinase. Active c-Abl kinase leads to Cdk5 tyrosine phosphorylation, and this phosphorylation is enhanced by Cables. Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity. Expression of antisense Cables in primary cortical neurons inhibited neurite outgrowth. Furthermore, expression of active Abl resulted in lengthening of neurites. The data provide evidence for a Cables-mediated interplay between the Cdk5 and c-Abl signaling pathways in the developing nervous system.

Amino Acid Sequence↗

PubMed2000

Reversibility of acute B-cell leukaemia induced by BCR-ABL1.

Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukaemias initiated by a chromosomal translocation. We have taken a new approach to determine if ablation of the genetic abnormality is sufficient for reversion by generating a conditional transgenic model of BCR-ABL1 (also known as BCR-ABL)-induced leukaemia. This oncogene is the result of a reciprocal translocation and is associated with different forms of leukaemia. The most common form, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukaemia (CML) and in up to 15% of adult patients with de novoacute lymphoblastic leukaemia (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance or by extremely long latency periods. One model uses the 'knock-in' approach to induce leukaemia by p190 BCR-ABL1(ref. 10). Given the limitations of models with p210, we used a different experimental approach. Lethal leukaemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1expression, even after multiple rounds of induction and reversion. Our results demonstrate that BCR-ABL1is required for both induction and maintenance of leukaemia.

Adult↗

PubMed2000

Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581.

The t(5;12)(q33;p13) translocation associated with chronic myelomonocytic leukemia (CMML) generates a TEL/PDGFbetaR fusion gene. Here, we used a murine bone marrow transplant (BMT) assay to test the transforming properties of TEL/PDGFbetaR in vivo. TEL/PDGFbetaR, introduced into whole bone marrow by retroviral transduction, caused a rapidly fatal myeloproliferative disease that closely recapitulated human CMML. TEL/PDGFbetaR transplanted mice developed leukocytosis with Gr-1(+) granulocytes, splenomegaly, evidence of extramedullary hematopoiesis, and bone marrow fibrosis, but no lymphoproliferative disease. We assayed mutant forms of the TEL/PDGFbetaR fusion protein - including 8 tyrosine to phenylalanine substitutions at phosphorylated PDGFbetaR sites to which various SH2 domain-containing signaling intermediates bind - for ability to transform hematopoietic cells. All of the phenylalanine (F-) mutants tested conferred IL-3-independence to a cultured murine hematopoietic cell line, but, in the BMT assay, different F-mutants displayed distinct transforming properties. In transplanted animals, tyrosines 579/581 proved critical for the development of myeloproliferative phenotype. F-mutants with these residues mutated showed no sign of myeloproliferation but instead developed T-cell lymphomas. In summary, TEL/PDGFbetaR is necessary and sufficient to induce a myeloproliferative disease in a murine BMT model, and PDGFbetaR residues Y579/581 are required for this phenotype.

Animals↗

PubMed1999

Dominant negative mutants implicate STAT5 in myeloid cell proliferation and neutrophil differentiation.

STAT5 is a member of the signal transducers and activation of transcription (STAT) family of latent transcription factors activated in a variety of cytokine signaling pathways. We introduced alanine substitution mutations in highly conserved regions of murine STAT5A and studied the mutants for dimerization, DNA binding, transactivation, and dominant negative effects on erythropoietin-induced STAT5-dependent transcriptional activation. The mutations included two near the amino-terminus (W255KR-->AAA and R290QQ-->AAA), two in the DNA-binding domain (E437E-->AA and V466VV-->AAA), and a carboxy-terminal truncation of STAT5A (STAT5A/triangle up53C) analogous to a naturally occurring isoform of rat STAT5B. All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and heterodimerized with STAT5B except for the WKR mutant, suggesting an important role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but not EE, were defective in transcriptional induction. The VVV mutant had a moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional activation, which was likely due to the formation of heterodimers that are defective in DNA binding. Interestingly, the WKR mutant had a potent dominant negative effect, comparable to the transactivation domain deletion mutant, triangle up53C. Stable expression of either the WKR or triangle up53C STAT5 mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both interleukin-3-dependent proliferation and granulocyte colony-stimulating factor (G-CSF)-dependent differentiation, without induction of apoptosis. Expression of these mutants in primary murine bone marrow inhibited G-CSF-dependent granulocyte colony formation in vitro. These results demonstrate that mutations in distinct regions of STAT5 exert dominant negative effects on cytokine signaling, likely through different mechanisms, and suggest a role for STAT5 in proliferation and differentiation of myeloid cells.

Amino Acid Sequence↗

PubMed1999

The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3-dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)-like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)-treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non- 5-FU-treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.

Animals↗

PubMed1999

Modulation of hepatic acute phase gene expression by epidermal growth factor and Src protein tyrosine kinases in murine and human hepatic cells.

As part of systemic inflammatory reactions, interleukin 6 (IL-6) induces acute phase protein (APP) genes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Epidermal growth factor (EGF), which contributes to the regenerative process after liver injury and also activates STATs, does not induce but attenuates IL-6-stimulated expression of several APP genes in primary mouse hepatocytes. The APP-modifying action of EGF receptor (EGFR) was characterized in HepG2 cells. Although EGF less effectively engages STAT proteins in these cells, it reduces expression of fibrinogen and haptoglobin, but stimulates production of alpha(1)-antichymotrypsin and induces transcription through the alpha(1)-antichymotrypsin and C-reactive protein promoter. The stimulatory EGFR signal is insensitive to inhibition of JAKs and appears to involve Src kinases and STAT proteins as shown by inhibition through overexpression of C-terminal Src kinase (Csk) and transdominant negative STAT3, respectively. A mediator role of Src is supported by the ability of c-Src and v-Src to activate STATs and induce transcription through APP promoters. Src kinases have been observed in association with the IL-6 receptor; however, inhibition of Src kinases by Csk enhances IL-6-induced transcription. The Csk effect is attributed to prevention of Src kinases from phosphorylating gp130 at the docking site for the signal-moderating protein tyrosine phosphatase SHP-2. The inhibitory EGFR signal on APP expression correlates with the activation of Erk1 and Erk2. The study shows a dual signaling function for EGFR and suggests that the ratio of receptor-activated STATs and Erks influence the level of stimulated or inhibited expression of individual APPs.

Acute-Phase Proteins↗

PubMed1999

Cycling, stressed-out and nervous: cellular functions of c-Abl.

c-Abl, the product of the cellular homologue of the transforming gene of Abelson murine leukaemia virus, has been a protein in search of a purpose for over two decades. Because c-Abl is implicated in the pathogenesis of several human leukaemias, understanding the functions of Abl is an important goal. Recently, biochemical and genetic approaches have converged to shed new light on the mechanism of regulation of c-Abl kinase activity and the multiple roles of c-Abl in cellular physiology. This review summarizes our current understanding of the many facets of c-Abl biology, emphasizing recent studies on Drosophila and mammalian Abl.

Animals↗