Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of cell proliferation is an important biologic function of interferons (IFNs), which has been exploited in therapeutic treatment of certain hematologic malignancies. However, the molecular mechanism was not clear. We have recently shown that IFNs (alpha/beta and gamma) inhibit protein kinase C (PKC)-dependent (such as PDGF and phorbol ester) but not PKC-independent (such as epidermal growth factor) activation of Raf-1 and mitogen-activated protein kinases (MAPK/ERKs) in fibroblasts (Xu et al, Mol Cell Biol 14:8018, 1994), suggesting a novel mechanism by which IFNs execute their antiproliferative function. Monocytes/macrophages are primary targets in vivo for IFN-gamma, the major activity of macrophage-activating factor. In the present study, mechanism of IFN-gamma-induced antiproliferative action in macrophages in response to colony-stimulating factor-1 (CSF-1) has been investigated. Our results show that antiproliferative effect of IFN-gamma overrode mitogenic effect of CSF-1 and phorbol ester, as measured by early gene expression, DNA synthesis and cell proliferation. Although activation, phosphorylation, and turnover of the CSF-1 receptor and CSF-1-induced increase in diacylglycerol production remained normal, IFN-gamma blocked CSF-1-stimulated activation of mitogen-activated protein kinases, Raf-1 kinase, increase in GTP-bound Ras and tyrosine phosphorylation, and activation of protein kinase C delta (PKC-delta). PKC-delta was required for CSF-1-induced mitogenic signaling and a primary target for IFN-gamma-induced inhibition. Interestingly, although phorbol myristate acetate stimulated Ras activation, PKC-delta did not appear to be an upstream activator of Ras. These studies clearly indicated that IFN-gamma specifically inhibits PKC-delta activation, resulting in blockage of the early events of mitogenesis in macrophages in response to CSF-1.
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PMID:Blockage of the early events of mitogenic signaling by interferon-gamma in macrophages in response to colony-stimulating factor-1. 870 28

The respiratory burst oxidase catalyzes the production of O2- by activated phagocytes and B lymphocytes. Activation is accomplished by any number of signal transduction pathways, and involves protein kinase C, MAP kinase, or both, and perhaps lipid-mediated pathways. Failure of O2- production is characteristic of chronic granulomatous disease, an inherited disorder of phagocyte function. A number of new mutations responsible for chronic granulomatous disease have been reported. O2- production is also altered in other diseases, most notably certain hematologic malignancies.
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PMID:The respiratory burst oxidase. 937 72

A series of alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation is considered to be the main cause of cancer. These mutational events include activation of oncogenes and inactivation of tumor suppressor genes. The elucidation of human cancer at the molecular level allows the design of rational, mechanism-based therapeutic agents that antagonize the specific activity of biochemical processes that are essential to the malignant phenotype of cancer cells. Because the frequency of RAS mutations is among the highest for any gene in human cancers, development of inhibitors of the Ras-mitogen-activated protein kinase pathway as potential anticancer agents is a very promising pharmacologic strategy. Inhibitors of Ras signaling have been shown to revert Ras-dependent transformation and cause regression of Ras-dependent tumors in animal models. The most promising new class of these potential cancer therapeutics are the farnesyltransferase inhibitors. The development of these compounds has been driven by the observation that oncogenic Ras function is dependent upon posttranslational modification, which enables membrane binding. In contrast to many conventional chemotherapeutics, farnesyltransferase inhibitors are remarkably specific and have been demonstrated to cause no gross systemic toxicity in animals. Some orally bioavailable inhibitors are presently being evaluated in phase II clinical trials. This review presents an overview on some inhibitors of the Ras signaling pathway, including their specificity and effectiveness in vivo. Because Ras signaling plays a crucial role in the pathogenesis of some hematologic malignancies, the potential therapeutic usefulness of these inhibitors is discussed. (Blood. 2000;96:1655-1669)
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PMID:Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? 1096 60

Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein kinase growth signaling in MM cells; induces apoptosis despite induction of p21 and p27 in both p53 wild-type and p53 mutant MM cells; overcomes drug resistance; adds to the anti-MM activity of dexamethasone; and overcomes the resistance to apoptosis in MM cells conferred by interleukin-6. PS-341 also inhibits the paracrine growth of human MM cells by decreasing their adherence to bone marrow stromal cells (BMSCs) and related nuclear factor kappaB-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy.
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PMID:The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. 1130 89

It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34(+) progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1- and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
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PMID:Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. 1175 88

Members of the nuclear receptor superfamily, including retinoic acid receptors (RARs), retinoid X receptors (RXRs), and vitamin D receptors (VDRs), are transcription factors that control many important cellular functions, and their ligands are widely used in several clinical indications. The latest family member is the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is highly expressed in normal monocytes, different leukemias, and epithelial malignancies. PPARgamma ligands have been developed and signal differentiation, growth arrest, and apoptosis. PPARgamma forms heterodimers with RXR, and ligation of both receptors is required for maximal signaling. PPARgamma signaling, its expression in hematologic malignancies, and role in differentiation are discussed. Interactions of PPARgamma with X-RARalpha, protein kinase R (PKR), PTEN, and mitogen-activated protein kinase (MAPK) have been described. PPARgamma ligands have been developed for the management of diabetes, but new and more potent ligands, including triterpenoids, are being investigated as therapeutic agents for epithelial and hematologic malignancies.
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PMID:Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies. 1204 3

R115777, a nonpeptidomimetic farnesyl transferase inhibitor has recently demonstrated a significant antileukemic activity in vivo in acute myeloid leukemia. Multiple myeloma (MM) is a fatal hematological malignancy characterized by an accumulation of long-lived plasma cells within the bone marrow. In the present study, we have investigated the effect of the R115777 on growth and survival of myeloma cells. We have found that R115777 induced (1) a significant and dose-dependent growth inhibition of the three myeloma cell lines tested; and (2) a significant and time-dependent apoptosis. R115777 also induced apoptosis in the bone marrow mononuclear cell population of four MM patients, being almost restricted to the malignant plasma cells. Finally, we have investigated the effect of the R115777 in the Ras/MAPK and JAK/STAT pathways which are implicated in survival and/or proliferation in MM. The phosphorylation of both STAT3 and ERK1/2 induced by IL-6 was totally blocked at 15 microM of R115777 and partially blocked when R115777 was used at 10 and 5 microM. The induction of apoptosis by R115777 in myeloma cells and its implication in the regulation of JAK/STAT signalling suggest that R115777 might be an interesting therapeutical approach in MM.
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PMID:Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. 1220 Jun 78

Fibroblast growth factor receptors (FGFRs) genes have been shown to be translocated in multiple myeloma (MM) and myeloproliferative disorder (MPD), indicating an important role for the FGFRs in hematologic malignancies. Here, we describe a novel splice variant of FGFR2 (FGFR2AT-I) arising from skipping exons 7-10 in human myeloid leukemia HL-60 cells, encoding a FGFR2 in which the Ig-like-III domain is deleted while the remainder of the mature molecule is fused in-frame to the transmembrane and COOH-terminal cytoplasmic kinases. Binding assays demonstrated that the FGFR2AT-I was able to bind FGF1, FGF2, and FGF7, leading to loss of ligand binding specificity. Furthermore, overexpression of FGFR2AT-I resulted in increased AKT and MAPK activation, conferring a survival advantage. Taken together, these findings indicate that the dysregulation of FGFRs' function by aberrant mRNA splicing contributes to tumor progression.
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PMID:A novel splice variant of fibroblast growth factor receptor 2 in human leukemia HL-60 cells. 1248 14

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell-type-specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)-dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked down-regulation of the MAP kinase kinase/extracellular regulatory kinase (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not induce apoptosis in IL-3-dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies.
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PMID:Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion. 1260 35

Mitogen-activated protein (Map) kinases are widely expressed serine-threonine kinases that mediate important regulatory signals in the cell. Three major groups of Map kinases exist: the p38 Map kinase family, the extracellular signal-regulated kinase (Erk) family, and the c-Jun NH2-terminal kinase (JNK) family. The members of the different Map kinase groups participate in the generation of various cellular responses, including gene transcription, induction of cell death or maintenance of cell survival, malignant transformation, and regulation of cell-cycle progression. Depending on the specific family isoform involved and the cellular context, Map kinase pathways can mediate signals that either promote or suppress the growth of malignant hematopoietic cells. Over the last few years, extensive work by several groups has established that Map kinase pathways play critical roles in the pathogenesis of various hematologic malignancies, providing new molecular targets for future therapeutic approaches. In this review, the involvement of various Map kinase pathways in the pathophysiology of hematologic malignances is summarized and the clinical implications of the recent advances in the field are discussed.
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PMID:Map kinase signaling pathways and hematologic malignancies. 1262 39


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