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)

Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
 ...
PMID:Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. 1059 2

We have demonstrated that a novel Ste20-related kinase, designated SLK, mediates apoptosis and actin stress fiber dissolution through distinct domains generated by caspase 3 cleavage. Overexpression of SLK in C2C12 myoblasts stimulated the disassembly of actin stress fibers and focal adhesions and induced apoptosis, as determined by annexin V binding and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling analysis. SLK was cleaved by caspase 3 in vitro and in vivo during c-Myc-, tumor necrosis factor alpha, and UV-induced apoptosis. Furthermore, cleavage of SLK released two domains with distinct activities: an activated N-terminal kinase domain that promoted apoptosis and cytoskeletal rearrangements and a C-terminus domain that disassembled actin stress fibers. Moreover, our analysis has identified a novel conserved region (termed the AT1-46 homology domain) that efficiently promotes stress fiber disassembly. Finally, transient transfection of SLK also activated the c-Jun N-terminal kinase signaling pathway. Our results suggest that caspase-activated SLK represents a novel effector of cytoskeletal remodeling and apoptosis.
 ...
PMID:Caspase 3 cleavage of the Ste20-related kinase SLK releases and activates an apoptosis-inducing kinase domain and an actin-disassembling region. 1061 Dec 47

The s-Myc is similar to c-Myc in its ability to induce apoptosis requiring caspase activation. However, s-Myc is distinct from c-Myc in that it has activity to suppress tumor growth and does not require wild-type p53 to induce apoptosis. These facts suggest differential regulation between s-Myc and c-Myc. Here we showed that s-Myc-mediated apoptosis triggered by UV was not inhibited by the inactive form mutant JNK (APF), though c-Myc-mediated apoptosis was. Moreover, we found that JNK did not affect the transactivation activity of s-Myc, but stimulated that of c-Myc. In contrast, both Myc-mediated apoptosis and caspase-3-like protease activation were suppressed by kinase-negative MKK6 and an inactive form mutant p38(AGF). Our results indicate that s-Myc does not require the JNK signaling unlike c-Myc during UV-triggered apoptosis, but the MKK6/p38MAPK pathway might regulate common apoptotic machinery for both s-Myc and c-Myc upstream of caspase.
 ...
PMID:Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. 1062 2

Recently we demonstrated that several flavonoids can inhibit the proliferation of certain human thyroid cancer cell lines. Among the flavonoids tested, apigenin and luteolin are the most effective inhibitors of these tumor cell lines. In the present study, we investigated the signal transduction mechanism associated with the growth inhibitory effect of apigenin, using a human anaplastic thyroid carcinoma cell line, ARO (UCLA RO-81-A-1). Using Western blot method, it was shown that the inhibitory effect of apigenin on ARO cell proliferation is associated with an inhibition of both EGFR tyrosine autophosphorylation and phosphorylation of its downstream effector mitogen activated protein (MAP) kinase. Protein levels of these signaling molecules were not affected. The inhibitor of phosphorylation by apigenin occurred within 30 min and continued for 4 h. A dose-dependent inhibition was demonstrable ranging from 12.5 microM to 50 microM. The level of phosphorylated c-Myc, a nuclear substrate for MAPK, was depressed from 16-48 h after apigenin treatment, finally leading to a programmed cell death involving DNA fragmentation. Furthermore, treatment with apigenin resulted in the inhibition of both anchorage-dependent and anchorage-independent thyroid cancer cell growth. In summary, apigenin is a promising inhibitor of signal transduction pathways that regulate the growth (anchorage-dependent and independent) and survival of human anaplastic thyroid cancer cells. Apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.
 ...
PMID:Signal pathways involved in apigenin inhibition of growth and induction of apoptosis of human anaplastic thyroid cancer cells (ARO). 1062 90

Cooperation of myc and activated ras has been suggested to cause malignant cell transformation but the mechanism is still unknown. Here we isolated a transformed cell line in which activation of c-Myc and Ras are independently controllable, and show that after establishment of the transformed state by c-myc and activated ras, removal of activated Ras initiates apoptosis that is dependent on c-Myc activity. Apoptosis is also initiated by an inhibitor of MEK (MAPK/ERK kinase), a kinase downstream of Ras, and apoptosis is blocked by activated Mek1. These results suggest that one of the conditions required for establishment of the transformed state is a block of apoptosis involving MEK activity. We tested the effect of MEK inhibition on cells transformed by various oncogenes. Suppression of apoptosis by MEK is not critical in general, but in cells transformed by c-myc plus a gene that activates the MAPK cascade it is necessary to avoid cell death. Activated Ras/MEK did not suppress c-myc-dependent apoptosis due to serum-limitation. Overexpression of chicken bcl-xL suppressed apoptosis under serum-limiting conditions, but not apoptosis initiated by Ras/MEK inhibition in cells transformed by myc and activated ras. Altogether, these results suggest the existence of a novel regulatory mechanism for myc-dependent apoptosis in certain transformed cells.
 ...
PMID:Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c-myc and activated ras. 1064 86

Recent studies have shown that during apoptosis protein synthesis is inhibited and that this is in part due to the proteolytic cleavage of eukaryotic initiation factor 4G (eIF4G). Initiation of translation can occur either by a cap-dependent mechanism or by internal ribosome entry. The latter mechanism is dependent on a complex structural element located in the 5' untranslated region of the mRNA which is termed an internal ribosome entry segment (IRES). In general, IRES-mediated translation does not require eIF4E or full-length eIF4G. In order to investigate whether cap-dependent and cap-independent translation are reduced during apoptosis, we examined the expression of c-Myc during this process, since we have shown previously that the 5' untranslated region of the c-myc proto-oncogene contains an IRES. c-Myc expression was determined in HeLa cells during apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. We have demonstrated that the c-Myc protein is still expressed when more than 90% of the cells are apoptotic. The presence of the protein in apoptotic cells does not result from either an increase in protein stability or an increase in expression of c-myc mRNA. Furthermore, we show that during apoptosis initiation of c-myc translation occurs by internal ribosome entry. We have investigated the signaling pathways that are involved in this response, and cotransfection with plasmids which harbor either wild-type or constitutively active MKK6, a specific immediate upstream activator of p38 mitogen-activated protein kinase (MAPK), increases IRES-mediated translation. In addition, the c-myc IRES is inhibited by SB203580, a specific inhibitor of p38 MAPK. Our data, therefore, strongly suggest that the initiation of translation via the c-myc IRES during apoptosis is mediated by the p38 MAPK pathway.
 ...
PMID:c-Myc protein synthesis is initiated from the internal ribosome entry segment during apoptosis. 1064 1

The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human tumours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intracellularly expressed, ER-targeted single-chain antibody (scFV-5R). Inducible expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line leads to loss of plasma membrane localized ErbB2. Simultaneously, the activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of the cell cycle. This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27Kip1 from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27KiP1 sequestration, decreased in the absence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We propose that c-Myc is a primary effector of ErbB2-mediated oncogenicity and functions to prevent normal p27Kip1 control of cyclinE/CDK2.
 ...
PMID:Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. 1076 21

Recently, glucose deprivation-induced oxidative stress has been shown to cause cytotoxicity, activation of signal transduction (i.e., ERK1, ERK2, JNK, and Lyn kinase), and increased expression of genes associated with malignancy (i.e., bFGF and c-Myc) in MCF-7/ADR human breast cancer cells. These results have led to the proposal that intracellular oxidation/reduction reactions involving hydroperoxides and thiols may provide a mechanistic link between metabolism, signal transduction, and gene expression in these human tumor cells. The current study shows that several other transformed human cell types appear to be more susceptible to glucose deprivation-induced cytotoxicity and oxidative stress than untransformed human cell types. In a matched pair of normal and SV40-transformed human fibroblasts the cytotoxic process is shown to be dependent upon ambient O2 concentration. A theoretical model to explain the results is presented and implications to unifying modern theories of cancer are discussed.
 ...
PMID:Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? 1086 52

The intracellularly acting protein toxin of Pasteurella multocida (PMT) causes numerous effects in cells, including activation of inositol 1,4,5-trisphosphate (IP(3)) signaling, Ca(2+) mobilization, protein phosphorylation, morphological changes, and DNA synthesis. The direct intracellular target of PMT responsible for activation of the IP(3) pathway is the G(q/11)alpha-protein, which stimulates phospholipase C (PLC) beta1. The relationship between PMT-mediated activation of the G(q/11)-PLC-IP(3) pathway and its ability to promote mitogenesis and cellular proliferation is not clear. PMT stimulation of p42/p44 mitogen-activated protein kinase occurs upstream via G(q/11)-dependent transactivation of the epidermal growth factor receptor. We have further characterized the effects of PMT on the downstream mitogenic response and cell cycle progression in Swiss 3T3 and Vero cells. PMT treatment caused dramatic morphological changes in both cell lines. In Vero cells, limited multinucleation, nuclear fragmentation, and disruption of cytokinesis were also observed; however, a strong mitogenic response occurred only with Swiss 3T3 cells. Significantly, this mitogenic response was not sustained. Cell cycle analysis revealed that after the initial mitogenic response to PMT, both cell types subsequently arrested primarily in G(1) and became unresponsive to further PMT treatment. In Swiss 3T3 cells, PMT induced up-regulation of c-Myc; cyclins D1, D2, D3, and E; p21; PCNA; and the Rb proteins, p107 and p130. In Vero cells, PMT failed to up-regulate PCNA and cyclins D3 and E. We also found that the initial PMT-mediated up-regulation of several of these signaling proteins was not sustained, supporting the subsequent cell cycle arrest. The consequences of PMT entry thus depend on the differential regulation of signaling pathways within different cell types.
 ...
PMID:Differential modulation and subsequent blockade of mitogenic signaling and cell cycle progression by Pasteurella multocida toxin. 1089 52

Eosinophilic meningitis or meningoencephalitis caused by Angiostrongylus cantonensis is endemic to the Pacific area of Asia, especially Taiwan, Thailand, and Japan. Although eosinophilia is an important clinical manifestation of A. cantonensis infection, the role of eosinophils in the progress of the infection remains to be elucidated. In this experiment, we showed that A. cantonensis-caused eosinoplia and inflammation might lead to the induction of NF-kappaB and protooncogene expression via activation of the tyrosine phosphorylation signal pathway. After mice were infected daily with 30 third-stage larvae of A. cantonensis by oral adminstration for 6 weeks, no significant differences PKC-alpha, MEK-1, ERK-2, JNK, and p38 protein expression were found between the control and infected mice. However, the protein tyrosine phosphorylation levels, NF-kappaB, and iNOS protein products were significantly increased by 3.5-, 3.3-, and 6.3-fold, respectively, after 3 weeks of A. cantonensis infection. The same pattern was found for c-Myc, c-Jun, and c-Fos proteins, which were elevated by 3.2-, 2.3-, and 3.4-fold, respectively, compared to control animals after 3 weeks. The expression potency of these proteins started increasing in week 1, reaching maximal induction in week 3, and then declining in week 5 after A. cantonensis infection. Another consistent result was noted in the pathological observations, including eosinophilia, leukocyte infiltration, granulomatous reactions, and time responses in brain tissues of infected mice. These data suggest that the development of brain injury by eosinophlia of A. cantonensis infection is associated with NF-kappaB and/or nuclear protooncogenes expression, which is activated by the tyrosine phosphorylation pathway.
 ...
PMID:Development of brain injury in mice by Angiostrongylus cantonensis infection is associated with the induction of transcription factor NF-kappaB, nuclear protooncogenes, and protein tyrosine phosphorylation. 1096 48


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