Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interferons (IFNs) are cytokines that play key roles in host defense against viral infections and immune surveillance against cancer. We report that BCR-ABL transformation of hematopoietic cells results in suppression of IFN-dependent responses, including transcription of IFN-inducible genes and generation of IFN-mediated antiviral effects. BCR-ABL transformation suppresses expression of several IFN-regulated genes containing IFN-sensitive response element (ISRE) or GAS elements in their promoters, including Isg15, Irf1, Irf9, and Ifit2 (interferon-induced protein with tetratricopeptide repeats 2). Suppression of transcription of ISRE-containing genes is also seen in cells expressing various BCR-ABL kinase domain mutants, including T315I, H396P, Y253F, and E255K, but not kinase-defective BCR-ABL. Such effects are associated with impaired IFN-dependent phosphorylation of Stat1 on Tyr(701) and Stat3 on Tyr(705) and defective binding of Stat complexes to ISRE or GAS elements. Beyond suppression of Stat activities, BCR-ABL inhibits IFN-inducible phosphorylation/activation of the p38 MAPK, suggesting a dual mechanism by which this abnormal fusion protein blocks IFN transcriptional responses. The inhibitory activities of BCR-ABL ultimately result in impaired IFNalpha-mediated protection against encephalomyocarditis virus infection and reversal of IFN-dependent growth suppression. Altogether, our data provide evidence for a novel mechanism by which BCR-ABL impairs host defenses and promotes malignant transformation, involving dual suppression of IFN-activated signaling pathways.
 ...
PMID:Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells. 1828 94

The mechanisms by which p210-BCR-ABL determines hematopoietic stem cells fate remain poorly understood. To better understand the behavior of BCR-ABL in pluripotent stem cells, we previously developed a murine embryonic stem (ES) cell model transformed by p210-BCR-ABL and reported that BCR-ABL activates STAT3, a major protein involved in ES cells self-renewal, which leads specifically to inhibition of ES cells differentiation. We show here that BCR-ABL either inhibits differentiation or, unexpectedly, induces a rapid commitment to differentiation of murine ES cells, according to the intracellular levels of activated STAT3. We show that inhibition of endogenous STAT3 activation with an inducible STAT3 protein with dominant-negative activity (STAT3F) results in an early, rapid and complete differentiation of BCR-ABL-expressing ES cells, whereas control ES cells retain a more undifferentiated phenotype. This phenomenon could be totally abrogated by PD98059, a specific MEK1 inhibitor, suggesting the involvement of mitogen-activated protein kinase (MAP-Kinase)/ERK1/2 pathway, which was found constitutively phosphorylated in BCR-ABL-expressing cells. In addition, BCR-ABL-expressing ES cells harboring low levels of activated STAT3 committed more rapidly through hematopoietic differentiation, since embryoid bodies (EBs) derived from these cells were able to generate numerous hematopoietic progenitors 2 days early. Moreover, BCR-ABL-expressing ES cells cultured first with low levels of activated STAT3 before EBs derivation displayed a more rapid loss of pluripotency than controls and failed to generate hematopoietic progenitors. This phenomenon was partially abrogated when ES cells were first exposed to PD98059 or to the tyrosine kinase inhibitor imatinib mesylate. From this predictive model, we suggest that variations of the activation levels in BCR-ABL substrates such as STAT3 may represent "instructive" secondary cooperating events involved in the transformation of the leukemic cell phenotype during the course of CML.
 ...
PMID:BCR-ABL induces opposite phenotypes in murine ES cells according to STAT3 activation levels. 1883 38

The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl-independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.
 ...
PMID:Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. 1907 21

Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH(2)-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.
 ...
PMID:Heat shock protein 90 as a drug target: some like it hot. 1911 27

Here we demonstrated that the 'loss of function' of not-rearranged c-ABL in chronic myeloid leukemia (CML) is promoted by its cytoplasmic compartmentalization bound to 14-3-3 sigma scaffolding protein. In particular, constitutive tyrosine kinase (TK) activity of p210 BCR-ABL blocks c-Jun N-terminal kinase (JNK) phosphorylation leading to 14-3-3 sigma phosphorylation at a critical residue (Ser(186)) for c-ABL binding in response to DNA damage. Moreover, it is associated with 14-3-3 sigma over-expression arising from epigenetic mechanisms (promoter hyper-acetylation). Accordingly, p210 BCR-ABL TK inhibition by the TK inhibitor Imatinib mesylate (IM) evokes multiple events, including JNK phosphorylation at Thr(183), p38 mitogen-activated protein kinase (MAPK) phosphorylation at Thr(180), c-ABL de-phosphorylation at Ser residues involved in 14-3-3 binding and reduction of 14-3-3 sigma expression, that let c-ABL release from 14-3-3 sigma and nuclear import, and address BCR-ABL-expressing cells towards apoptotic death. Informational spectrum method (ISM), a virtual spectroscopy method for analysis of protein interactions based on their structure, and mathematical filtering in cross spectrum (CS) analysis identified 14-3-3 sigma/c-ABL binding sites. Further investigation on CS profiles of c-ABL- and p210 BCR-ABL-containing complexes revealed the mechanism likely involved 14-3-3 precluded phosphorylation in CML cells.
 ...
PMID:14-3-3 ligand prevents nuclear import of c-ABL protein in chronic myeloid leukemia. 1922 Aug 9

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.
 ...
PMID:Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells. 1929 93

Constitutive tyrosine kinase (TK) activity of p210 BCR-ABL fusion protein of chronic myeloid leukemia (CML) usurps physiological functions of normal p145 c-ABL protein. Accordingly, its inhibition by imatinib mesylate (IM) lets p145 c-ABL translocate into the nuclear compartment, which drives cell growth arrest and apoptotic death. Here we show that IM and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (Everolimus) have additive effects on BCR-ABL-expressing cells. Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c-ABL through events encompassing post-translational modifications of p145 c-ABL (Thr(735) phosphorylation) precluding its nuclear export and of 14-3-3 sigma (Ser(186) phosphorylation by c-Jun N-terminal kinase [JNK]) promoting p145 c-ABL nuclear re-import.
 ...
PMID:mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. 1964 77

Aberrant signaling causes many diseases, and manipulating signaling pathways with kinase inhibitors has emerged as a promising area of drug research. Most kinase inhibitors target the conserved ATP-binding pocket; therefore specificity is a major concern. Proteomics has previously been used to identify the direct targets of kinase inhibitors upon affinity purification from cellular extracts. Here we introduce a complementary approach to evaluate the effects of kinase inhibitors on the entire cell signaling network. We used triple labeling SILAC (stable isotope labeling by amino acids in cell culture) to compare cellular phosphorylation levels for control, epidermal growth factor stimulus, and growth factor combined with kinase inhibitors. Of thousands of phosphopeptides, less than 10% had a response pattern indicative of targets of U0126 and SB202190, two widely used MAPK inhibitors. Interestingly, 83% of the growth factor-induced phosphorylation events were affected by either or both inhibitors, showing quantitatively that early signaling processes are predominantly transmitted through the MAPK cascades. In contrast to MAPK inhibitors, dasatinib, a clinical drug directed against BCR-ABL, which is the cause of chronic myelogenous leukemia, affected nearly 1,000 phosphopeptides. In addition to the proximal effects on ABL and its immediate targets, dasatinib broadly affected the downstream MAPK pathways. Pathway mapping of regulated sites implicated a variety of cellular functions, such as chromosome remodeling, RNA splicing, and cytoskeletal organization, some of which have been described in the literature before. Our assay is streamlined and generic and could become a useful tool in kinase drug development.
 ...
PMID:Global effects of kinase inhibitors on signaling networks revealed by quantitative phosphoproteomics. 1965 22

Chronic myeloid leukemia (CML) is a neoplastic disease of the hematopoietic stem cell. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) may up-regulate the transcriptional activity of some oncogenes in cancerous cells. The aim of this study was to verify the expression pattern of hnRNPK in patients with CML, to explore its association with BCR-ABL and some abnormal signaling pathways, and to discover how hnRNPK contributes to the progression of CML. In this study, 15 patients with CML (9 in chronic phase and 6 in blast crisis) were enrolled in this study. The expression of hnRNPK in mononuclear cells (MNCs) from these patients was detected by Western blotting and fluorimeter-based quantitative real-time reverse transcriptase polymerase chain reaction. hnRNPK expression levels in K562 cell line and imatinib-resistant leukemic cell line K562R, following the treatments with the inhibitors of Ras-MAPK (PD98059), PI3K/AKT (LY294002), JAK/STAT (AG490) signaling pathways, and BCR-ABL [imatinib mesylate (IM)], were also determined. As the results, the overexpression of hnRNPK in protein and gene patterns was detected in MNCs from patients with CML comparing with normal donors. Especially, its level in MNCs from patients with CML-blast crisis was significantly higher than in CML-chronic phase cells (P < 0.01). After the treatment with PD98059 (at 4, 8, 24, and 48 h) and IM (at 48 h), the expression levels of hnRNPK in leukemic cell lines were decreased, comparing with DMSO control group (P < 0.05). In conclusion, the results suggest that the overexpression of hnRNPK, which is regulated by BCR-ABL and Ras-MAPK signaling pathways, may promote the progression of CML. hnRNPK would be a potential marker and therapeutic target of CML evolution.
 ...
PMID:The role of heterogeneous nuclear ribonucleoprotein K in the progression of chronic myeloid leukemia. 1965 39

The BCR-ABL tyrosine kinase is the defining feature of chronic myeloid leukemia (CML) and its kinase activity is required for induction of this disease. Current thinking holds that BCR-ABL forms a multi-protein complex that incorporates several substrates and adaptor proteins and is stabilized by multiple direct and indirect interactions. Signaling output from this highly redundant network leads to cellular transformation. Proteins known to be associated with BCR-ABL in this complex include: GRB2, c-CBL, p62(DOK), and CRKL. These proteins in turn, link BCR-ABL to various signaling pathways indicated in cellular transformation. In this study we show that a triple mutant of BCR-ABL with mutations of the direct binding sites for GRB2, CBL, p62(DOK) and CRKL, is defective for transformation of primary hematopoietic cells in vitro and in a murine CML model, while it retains the capacity to induce IL-3 independence in 32D cells. Compared to BCR-ABL, the triple mutant's ability to activate the MAP kinase and PI3-kinase pathways is severely compromised, while STAT5 phosphorylation is maintained, suggesting that the former are crucial for the transformation of primary cells, but dispensable for transformation of factor dependent cell lines. Our data suggest that inhibition of BCR-ABL-induced leukemia by disrupting protein interactions could be possible, but would require blocking of multiple sites.
 ...
PMID:A BCR-ABL mutant lacking direct binding sites for the GRB2, CBL and CRKL adapter proteins fails to induce leukemia in mice. 1982 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>