Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcitriol or 1,25-dihydroxycholecalciferol (vitamin D) is classically known for its effects on bone and mineral metabolism. Epidemiological data suggest that low vitamin D levels increase the risk and mortality from prostate cancer. Calcitriol is also a potent anti-proliferative agent in a wide variety of malignant cell types including prostate cancer cells. In prostate model systems (PC-3, LNCaP, DU145, MLL) calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol's effects are associated with an increase in cell cycle arrest, apoptosis, differentiation and in the modulation of growth factor receptors. Calcitriol induces a significant G0/G1 arrest and modulates p21(Waf/Cip1) and p27(Kip1), the cyclin dependent kinase inhibitors. Calcitriol induces PARP cleavage, increases the bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs, P-Erk-1/2) and phosphorylated Akt (P-Akt), induces caspase-dependent MEK cleavage and up-regulation of MEKK-1, all potential markers of the apoptotic pathway. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In combination with calcitriol, dexamethasone results in a significant time- and dose-dependent increase in VDR protein and an enhanced apoptotic response as compared to calcitriol alone. Calcitriol can also significantly increase cytotoxic drug-mediated anti-tumor efficacy. As a result, phase I and II trials of calcitriol either alone or in combination with the carboplatin, paclitaxel, or dexamethasone have been initiated in patients with androgen-dependent and -independent prostate cancer and advanced cancer. Patients were evaluated for toxicity, maximum tolerated dose (MTD), schedule effects, and PSA response. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the MTD is still being delineated and dexamethasone or paclitaxel appear to ameliorate toxicity. Studies continue to define the MTD of calcitriol whichcan be safely administered on this intermittent schedule either alone or with other agents and to evaluate the mechanisms of calcitriol effects in prostate cancer.
 ...
PMID:Vitamin D-related therapies in prostate cancer. 1246 54

Helicobacter pylori induces activation of mitogen-activated protein kinases (MAPKs). However, its effect on H. pylori-induced apoptosis has not been evaluated. Thus, we examined whether H. pylori-induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 MAPK activation affects gastric epithelial cell apoptosis and bcl-2 family gene expression, especially in relation to the cagA status of an H. pylori strain. In flow cytometric and oligonucleosome-bound DNA enzyme-linked immunosorbent assay analyses, infection with cagA(+) H. pylori strains induced gastric cancer cell apoptosis in AGS cells more prominently than infection with cagA mutants. Activation of ERK1/2 and p38 MAPKs was also more prominent in cagA(+) strains. Pretreatment with a MEK inhibitor (PD98059) inhibited ERK1/2 activation and increased H. pylori-induced apoptosis significantly. This increased apoptosis was accompanied by decreased antiapoptotic bcl-2 mRNA expression among bcl-2-related genes (bcl-2, bax, bak, mcl-1, and bcl-X(L/S)), and the effect was also more prominent in the cagA(+) strains. However, the alteration of bcl-2 gene expression was not accompanied by protein level changes. Inhibition of p38 using specific inhibitor SB203580 decreased H. pylori-induced apoptosis but resulted in little alteration of bcl-2-related gene expression. In conclusion, H. pylori-induced ERK1/2 activation, especially by the cagA(+) H. pylori strain, may play a protective role against gastric epithelial cell apoptosis partially through maintenance of bcl-2 gene expression.
 ...
PMID:Effect of inhibition of extracellular signal-regulated kinase 1 and 2 pathway on apoptosis and bcl-2 expression in Helicobacter pylori-infected AGS cells. 1254 May 63

Apoptosis of renal tubular epithelial cells plays a major role in acute renal failure. Several external and internal signals can induce apoptosis, which is then effectuated via several pathways. These pathways are either the FAS/FAS-L pathway and downstream MAPK (mitogen-activated protein kinases) and JNK (c-Jun N-terminal kinase) signal transduction, or the RANK/RANK-L (receptor activator of NFkB) pathway via activation of the caspase cascade. Other pathways, especially for apoptosis induction by toxins, include the mitochondrial permeability transition pore activation and Bcl-2 superfamily member differential regulation. An important final, irreversible branch of these pathways is the release of cytochrome c from the mitochondria, leading to nuclear fragmentation. Therapeutic interventions of acute tubular injury focus on the prevention of apoptosis by either modulation of the balance of the bcl-2 family or by selectively blocking angiotensin receptors. It is not clear yet, which receptor blockade or combination of receptor blockers are most effective in apoptosis prevention. In chronic renal failure, tubular apoptosis has been found in biopsies from polycystic kidneys, but not in a quantitatively meaningful amount in other chronic human renal diseases. On the other hand, given the short half-life of apoptotic cells of few hours, even low numbers over time might turn out to be important modulators of chronic kidney disease, which are characterized by tubular cell loss. Potential therapeutic interventions to prevent tubular apoptosis in chronic renal disease include angiotensin system inhibition, whereby the angiotensin II AT2 receptor blockade seems more promising in apoptosis inhibition than the inhibition of other receptor subtypes.
 ...
PMID:Tubular apoptosis in the pathophysiology of renal disease. 1260 10

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that lithium and valproate have recently been demonstrated to robustly increase the expression of the cytoprotective protein bcl-2 (an abbreviation for the B-cell lymphoma/leukemia-2 gene) in the CNS in vivo and in cells of human neuronal origin. Lithium and valproate also robustly activate a signaling cascade utilized by endogenous growth factors-the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. Complementary human studies have shown that chronic lithium administration significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. These unique and unexpected properties of lithium and valproate suggest that they may have broader utility as adjunctive agents in the treatment of a variety of neuropsychiatric disorders associated with cell atrophy or loss. The adjunctive use of these agents-at low doses-may provide the trophic support necessary to restore, enhance, and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal functioning.
 ...
PMID:The use of mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders. 1272 Apr 79

A substantial body of data from clinical and laboratory studies indicates that reactive oxygen intermediates are implicated in the pathogenesis of diverse human diseases, including cancer, diabetes, and neurodegenerative disorders. Oxidative stress induced by reactive oxygen intermediates often causes cell death via apoptosis that is regulated by a plenty of functional genes and their protein products. Bcl-2, which is an integral intermitochondrial membrane protein, blocks apoptosis induced by a wide array of death signals. In spite of extensive research, the molecular milieu that characterizes the antiapoptotic function of Bcl-2 is complex and not fully identified. Recently, there are several lines of evidence that Bcl-2 functions via antioxidant pathways to prevent apoptosis. Thus, bcl-2-overexpressing cells exhibit elevated expression of antioxidant enzymes and higher levels of cellular GSH compared with the control cells transfected with the vector alone. There has been increasing evidence supporting that the redox-sensitive transcription factor nuclear factor kappaB regulates the activity and/or expression of antioxidative and antiapoptotic target genes and promotes cell survival against oxidative cell death. This commentary focuses on the antioxidative functions of Bcl-2 and underlying molecular mechanisms in relation to its antiapoptotic property. The role of Bcl-2 in regulation of nuclear factor kappaB signaling pathways and possible cross-talk with mitogen-activated protein kinases are also discussed.
 ...
PMID:Potentiation of cellular antioxidant capacity by Bcl-2: implications for its antiapoptotic function. 1455 11

Cardioprotective mechanisms such as acute or early preconditioning activate several primary signaling pathways that seem to converge on mitochondrial targets, leading to altered cell metabolism and inhibition of apoptosis. Acute preconditioning leads to generation of agonists, which bind to G protein-coupled receptors, and initiates a signaling cascade that involves activation of phosphoinositide-3-kinase, endothelial NO synthase, protein kinase C, glycogen synthase kinase 3beta, mitogen-activated protein kinases, and other signaling pathways. Activation of these signaling pathways along with generation of reactive oxygen species leads to alterations in the activity of key mitochondrial proteins such as mitochondrial ATP-sensitive K(+) channels, the mitochondrial permeability transition pore, and bcl-2 family members. Alterations in these mitochondrial proteins results in altered metabolism and inhibition of cell death, thus resulting in cardioprotection.
 ...
PMID:Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. 1471 31

Antiapoptotic members of the bcl-2 family have recently been implicated in the pathogenesis of chronic myeloid leukemia (CML), a hematopoietic neoplasm associated with the BCR/ABL oncogene. We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed myeloid cell leukemia-1 (mcl-1) mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL inhibitor imatinib (=STI571) decreased the expression of MCL-1 in these cells. Correspondingly, BCR/ABL enhanced mcl-1 promoter activity, mcl-1 mRNA expression, and the MCL-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of MCL-1 in Ba/F3 cells was counteracted by the mitogen-activated protein-kinase/extracellular signal-regulated kinase (MEK) inhibitor, PD98059, but not by the phosphoinositide 3-kinase inhibitor, LY294002. Identical results were obtained for constitutive expression of MCL-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of MCL-1 as a survival-related target in CML cells, mcl-1 siRNA and mcl-1 antisense oligonucleotides (ASOs) were applied. The resulting down-regulation of MCL-1 was found to be associated with a substantial decrease in viability of K562 cells. Moreover, the mcl-1 ASO was found to synergize with imatinib in producing growth inhibition in these cells. Together, our data identify MCL-1 as a BCR/ABL-dependent survival factor and interesting target in CML.
 ...
PMID:Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. 1562 46

Protein phosphatases have been classified into two basic types, namely protein serine/threonine phosphatase (PP), and protein tyrosine phosphatase (PTP). Cpd 5 is a selective inhibitor of cdc25 phosphatases, which belong to members of PTPs and regulate cell proliferation by controlling cyclin-dependent kinases (cdks). The present study was undertaken to investigate the potential utility of Cpd 5 as an anti-neoplastic agent for renal cell carcinomas (RCCs). Three renal cancer cell lines, 769P, Sw839, and A498 were used. The effects of Cpd 5 on the viability of renal cancer cell lines was analyzed using an Alamar Blue assay. Apoptosis was determined by flow cytometric TUNEL analysis. Changes in the expression of cdc25 phosphatases, mitogen-activated protein kinases (MAPKs), and bcl-2 family proteins were detected using Western blot analysis. The apoptosis-inducing effect of Cpd 5 on human RCC tissue was analyzed through TUNEL staining of organ cultures from RCCs. Cpd 5 showed a strong cytotoxicity against all renal cancer cell lines with an apoptosis-inducing effect. All cell lines treated with Cpd 5 resulted in a down-regulation of cdc25A, cdc25B, and cdc25C, however, the MAPK pathways were not affected. In addition, the up-regulation of bax, and the down-regulation of bcl-2 and bcl-xL, was observed. In organ cultures from RCCs, TUNEL-positive apoptotic nuclei were observed when treated with Cpd 5. Cpd 5 was thus found to effectively inhibit the proliferation of human renal cancer cells while also inducing apoptosis by inhibiting cdc25 phosphatases and modulating bcl-2 family proteins. The administration of Cpd 5 may thus be an effective therapeutic approach for RCCs.
 ...
PMID:Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. 1607 67

Bipolar disorder is a devastating disease with a lifetime incidence of about 1% in the general population. Suicide is the cause of death in 10 to 15% of patients and in addition to suicide, mood disorders are associated with many other harmful health effects. Mood stabilizers are medications used to treat bipolar disorder. In addition to their therapeutic effects for the treatment of acute manic episodes, mood stabilizers are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. The most established and investigated mood-stabilizing drugs are lithium and valproate but other anticonvulsants (such as carbamazepine and lamotrigine) and antipsychotics are also considered as mood stabilizers. Despite the efficacy of these diverse medications, their mechanisms of action remain, to a great extent, unknown. Lithium's inhibition of some enzymes, such as inositol monophosphatase and glycogen synthase kinase-3, probably results in its mood-stabilizing effects. Valproate may share its anticonvulsant target with its mood-stabilizing target or may act through other mechanisms. It has been shown that lithium, valproate, and/or carbamazepine regulate numerous factors involved in cell survival pathways, including cyclic adenine monophospate response element-binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen-activated protein kinases. These drugs have been suggested to have neurotrophic and neuroprotective properties that ameliorate impairments of cellular plasticity and resilience underlying the pathophysiology of mood disorders. This article also discusses approaches to develop novel treatments specifically for bipolar disorder.
 ...
PMID:Mood stabilizers target cellular plasticity and resilience cascades: implications for the development of novel therapeutics. 1621 81

We have demonstrated that cationic liposomes composed of stearylamine (SA-liposomes) induce apoptosis in a variety of cells, but the mechanism responsible for the cellular death is not clear. In this paper, we investigated the signaling pathways implicated in SA-liposome-induced apoptosis in the macrophage-like cell line RAW264.7. Treatment with SA-liposomes caused the activation of mitogen-activated protein kinases (MAPKs), especially p38 and c-jun N-terminal kinase, and apoptosis was only inhibited upon the addition of a specific inhibitor for p38. N-acetylcysteine, a scavenger of reactive oxygen species (ROS), effectively inhibited the activation of p38 and cellular death, indicating that the activation induced by ROS is an initial step in the process of apoptosis triggered by SA-liposomes. Caspase-8 was activated by p38, and caspase-8-dependent cleavage of Bid was also observed. No down-regulation of bcl-2 expression, and no cleavage of Bax protein were observed. Taken together, our results suggest that apoptosis of RAW264.7 by SA-liposomes was mediated by the MAPK p38 and a caspase-8-dependent Bid-cleavage pathway. Moreover, we found that ROS can contribute intimately to the SA-liposome-induced cell death in RAW264.7.
 ...
PMID:Cationic liposomes induce apoptosis through p38 MAP kinase-caspase-8-Bid pathway in macrophage-like RAW264.7 cells. 1627 97


<< Previous 1 2 3 Next >>