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)

We recently improved an in vitro ischemic model, using PC12 neuronal cultures exposed to oxygen-glucose deprivation (OGD) for 3 hr in a special device, followed by 18 hr of reoxygenation. The cell death induced in this ischemic model was evaluated by a series of markers: lactate dehydrogenase (LDH) release, caspase-3 activation, presence of cyclin D1, cytochrome c leakage from the mitochondria, BAX cellular redistribution, cleavage of poly (ADP-ribose) polymerase (PARP) to an 85-kDa apoptotic fragment, and DNA fragmentation. The OGD insult, in the absence of reoxygenation, caused a strong activation of the mitogen-activated protein kinase (MAPK) isoforms extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and stress-activated protein kinase (SAPK), also known as p-38. The detection of apoptotic markers and activation of MAPKs during the ischemic insult strongly suggest that apoptosis plays an important role in the PC12 cell death. Homocarnosine, a neuroprotective histidine dipeptide, present in high concentrations in the brain, was found to provide neuroprotection, as expressed by a 40% reduction in LDH release and caspase-3 activity at 1 mM. Homocarnosine reduced OGD activation of ERK 1, ERK 2, JNK 1, and JNK 2 by 40%, 46%, 55%, and 30%, respectively. These results suggest that apoptosis is an important characteristic of OGD-induced neuronal death and that antioxidants, such as homocarnosine, may prevent OGD-induced neuronal death by inhibiting the apoptotic process and/or in relation to the differential attenuation of activity of MAPKs.
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PMID:Apoptotic characteristics of cell death and the neuroprotective effect of homocarnosine on pheochromocytoma PC12 cells exposed to ischemia. 1474 33

Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nm. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH(2) terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.
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PMID:Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells. 1504 68

Recently, we demonstrated that the cyclooxygenase-2 (COX-2) inhibitor celecoxib acts to significantly suppress the growth of rat C611B cholangiocarcinoma (ChC) cells in vitro. To establish a molecular mechanism for this growth suppression, we investigated the effects of celecoxib on apoptotic signaling pathways in cultured rat C611B ChC cells. Celecoxib and another COX-2 inhibitor, rofecoxib, at 5 microM were almost equally effective in inhibiting prostaglandin E(2) (PGE(2)) production by these cells, but at this low concentration, neither inhibitor suppressed growth or induced apoptosis. Celecoxib at 50 microM induced prominent apoptosis in these cells, whereas rofecoxib at 50 microM was without effect in either suppressing growth or inducing apoptosis. Celecoxib (50 microM) did not alter Bcl-2, Bcl-x(L), or COX-2 protein levels, nor did it inhibit p42/44 mitogen-activated protein kinase (MAPK) phosphorylation; however, it significantly suppressed serine/threonine kinase Akt/PKB (Akt) phosphorylation and kinase activity in cultured C611B cells. This effect, in turn, directly correlated with Bax translocation to mitochondria, cytochrome c release into cytosol, activation of caspase-9 and caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Addition of 25 microM PGE(2) to C611B cell cultures blocked the apoptotic actions of celecoxib. Rofecoxib (50 microM) was without effect in suppressing Akt phosphorylation and caspase-3 activation. In vivo, celecoxib partially suppressed tumorigenic growth of C611B ChC cells. In conclusion, our results indicate that celecoxib preferentially acts in vitro to induce apoptosis in ChC cells through a mechanism involving Akt inactivation, Bax translocation, and cytochrome c release. Our in vivo results further suggest celecoxib might have potential therapeutic or chemopreventive value against ChC.
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PMID:Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation. 1505 7

The dual Ser/Thr kinase MKK4 and its downstream targets JNK and p38 regulate critical cellular functions during embryogenesis and development. MKK4 has been identified as a putative tumor-suppressor gene in human solid tumors of breast, prostate and pancreas. To clarify the mechanisms underlying the transforming potential of molecular defects targeting MKK4, we have generated totipotent embryonic stem (ES) cells expressing the dominant-negative mutant DN-MKK4(Ala), S257A/T261A. Stably transfected DN-MKK4-ES cells exhibit a transformed fibroblast-like morphology, reduced proliferation rate, were no more submitted to cell contact inhibition, were growing in soft agar, and were much more tumorigenic than parental ES cells in athymic nude mice. These phenotypic changes: (i) are consistent with the protection of DN-MKK4-transfected ES cells from spontaneous, cell density-dependent, and stress-induced apoptosis (DAPI staining and poly (ADP-ribose) polymerase (PARP) cleavage) and (ii) correlated with alterations in JNK, p38, and Erk-1/-2 MAPK/SAPK signaling. Taken together, our data provide a new mechanism linking the MKK4 signaling pathways to cancer progression and identify MKK4 as a tumor-suppressor gene implicated in several transforming functions.
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PMID:Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. 1512 34

LIGHT is a member of tumor necrosis factor (TNF) superfamily, and previous studies have indicated that in the presence of interferon-gamma (IFN-gamma), LIGHT through LTbetaR signaling can induce cell death with features unlike classic apoptosis. In present study, we investigated the mechanism of LIGHT/IFN-gamma-induced cell death in HT-29 cells, where the cell death was profoundly induced when sub-toxic concentrations of LIGHT and IFN-gamma were co-treated. LIGHT/IFN-gamma-induced cell death was accompanied by DNA fragmentation and slight LDH release. This effect was not affected by caspase, JNK nor cathepsin B inhibitors, but was partially prevented by p38 mitogen-activated protein kinase (MAPK) and poly (ADP-ribose) polymerase (PARP) inhibitors, and abolished by aurintricarboxylic acid (ATA), which is an inhibitor of endonuclease and STATs signaling of IFN-gamma. Immunobloting reveals that LIGHT/IFN-gamma could induce p38 MAPK activity, Bak and Fas expression, but down-regulate Mcl-1. Besides, LIGHT/IFN-gamma could not activate caspase-3 and -9, but decreased mitochondrial membrane potential. Although LIGHT could not affect IFN-gamma-induced STAT1 phosphorylation and transactivation activity, which was required for the sensitization of cell death, survival NF-kappaB signaling of LIGHT was inhibited by IFN-gamma. These data suggest that co-presence of LIGHT and IFN-gamma can induce an integrated interaction in signaling pathways, which lead to mitochondrial dysfunction and mix-type cell death, not involving caspase activation.
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PMID:Mechanism of LIGHT/interferon-gamma-induced cell death in HT-29 cells. 1548 69

We have previously reported that murine peritoneal macrophages exposed to ultraviolet B (UV-B; 100 mJ/cm2) undergo apoptosis, as indicated by alterations in cell morphology, caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, sustained activation of p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) and inactivation of p42/44 MAPKs. It is now reported that macrophages undergoing UV-B-induced apoptosis show enhanced expression of protein kinase Cdelta (PKCdelta) in a time-dependent manner. Pretreatment of macrophages with PKCdelta-specific inhibitor rottlerin prior to the UV-B irradiation inhibits activation of caspase-3, PARP cleavage, DNA fragmentation and release of intracellular Ca2+. Inhibition of PKCdelta also blocks the sustained activation of p38 and JNK MAPKs as well as inactivation of p42/44 MAPKs. PKCalpha and PKCbeta1 expression also increases during UV-B-induced apoptosis in macrophages. Inhibition of these two isoforms with Go6976 slightly suppresses caspase-3 activation, PARP cleavage, DNA fragmentation and release of intracellular Ca2+, but has no effect on the sustained activation of p38/JNK MAPKs or inactivation of p42/44 MAPKs. It is, therefore, suggested that activation of PKCdelta might play an important role in the UV-B-induced apoptosis and that specific activated isoforms of PKC may have distinct functions in cell death.
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PMID:Role of protein kinase Cdelta in UV-B-induced apoptosis of macrophages in vitro. 1556 68

Anthocyanidins that are reddish pigments widely distributed in fruit and vegetables have been reported to possess antioxidant and anticancer activities. To understand the molecular basis of the putative anticancer activity of anthocyanidins, we investigated the antiproliferation effects of anthocyanidins in human hepatoma cell lines. Delphinidin, cyanidin, and malvidin exhibited strong growth inhibitory effects against human hepatoma HepG(2), but were less effective against Hep3B. According to the appearance of the caspase-3 fragments and stimulated proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) in time-dependent studies, delphinidin induced apoptotic cell death characterized by internucleosomal DNA fragmentation and caused a rapid induction of caspase-3 activity. RT-PCR and Western blot data revealed that delphinidin stimulated an increase in the c-Jun and JNK phosphorylation expression at mRNA and protein levels, respectively. Moreover, delphinidin-induced apoptotic cell death was accompanied by up-regulation of Bax and down-regulation of Bcl-2 protein. Dephinidin-induced DNA fragmentation was blocked by N-acetyl-l-cysteine and catalase, suggesting that the death signaling was triggered by oxidative stress. Our experiments provide evidence that delphinidin is an effective apoptosis inducer in HepG(2) cells through regulation of Bcl-2 family moleculars and activation of c-Jun N-terminal kinase cascade. The results suggest that induction of apoptosis by anthocyanidins is a pivotal mechanism of their cancer chemopreventive functions.
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PMID:Induction of apoptosis by the Anthocyanidins through regulation of Bcl-2 gene and activation of c-Jun N-terminal kinase cascade in hepatoma cells. 1574 68

Lactoferrin, a member of the transferrin family, is iron-binding and a strongly cationic 76 kDa glycoprotein. In breast milk it is secreted in high concentrations from glandular epithelia and is also present in other exocrine fluids including saliva. In the present study, we examined the biological mechanisms of apoptosis induced by pepsin-digested-lactoferrin peptide (Lfn-p) in the human oral squamous cell carcinoma cell line SAS. We found that treatment with Lfn-p induced cell death with apoptotic nuclear changes, preceded by the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in the apoptotic cells. Treatment with Lfn-p induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), a member of the MAP kinase family, at early stages of apoptosis. Another MAP kinase, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), was also phosphorylated by treatment with Lfn-p. Pretreatment of SAS cells with SP600125, a JNK/SAPK inhibitor, diminished Lfn-induced apoptosis, as assessed by determining released lactate dehydrogenase activity. On the other hand, the MEK1 inhibitors PD98059 or U0126 showed no effect on repression of cell death, but rather an increase. These results suggest that JNK/SAPK activation may play an important role in Lfn-p-induced apoptotic cell death of human oral squamous cell carcinoma cells.
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PMID:Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. 1587 78

Cervical cancer is a leading cause of death in developing countries and is the second highest occurring cancer in women all over the world. The progression of cancer is a multistep process affecting aspects of cellular function such as proliferation, differentiation and apoptosis. Mitogen activated protein kinases (MAPKs), which include p38-MAPK, c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinases (ERKs) are closely associated with cell proliferation and apoptosis and the balance between them could determine a cell's fate. Despite the expanding research effort in vitro, little is known about MAPK activation in clinical specimens of cervical cancer. Therefore, the aim of this ex vivo study was to correlate the phosphorylation status (activity) of MAPKs (p38-MAPK, JNK and ERK), as well as poly (ADP-ribose) polymerase (PARP) and caspase-3 (two cellular markers of apoptosis), during the different stages of cervical carcinogenesis, to observe whether correlations between MAPK activities and apoptosis during the disease process exist. Decreased p38-MAPK phosphorylation was found in the carcinoma (Ca) group) compared to the normal tissues, as well when the low grade squamous intraepithelial lesion--LSIL) group and high grade squamous intraepithelial lesion--HSIL) group were compared with the Ca group. Interestingly, a significant decrease in ERK44 phosphorylation was observed in Ca when compared to LSIL and HSIL. There was also a significant decrease in JNK phosphorylation in Ca when compared with normal tissue and HSIL. As expected, caspase-3 activation and PARP cleavage was significantly lower in Ca when compared with normal tissue. Our results present the first evidence of in vivo involvement of MAPKs in cervical cancer and indicate a possible correlation between MAPK activities and apoptosis in the disease process.
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PMID:Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis. 1592 65

Defective heme synthesis may cause acute porphyrias, which are associated with a wide array of neurological disturbances involving both the central and peripheral nervous systems. Thus, the understanding of the roles of heme in neuronal cell function may provide insights into the molecular events underlying the pathogenesis of neuropathies associated with defective heme synthesis. In this report, we use rat pheochromocytoma (PC12) clonal cells as a model system for studying the role of heme in neuronal cell survival. We examined the effects of inhibition of heme synthesis on signaling pathways and gene expression in nerve growth factor (NGF)-induced PC12 cells. We found that succinyl acetone-induced heme deficiency selectively caused apoptosis in NGF-induced PC12 cells. Further, we found that in succinyl acetone-treated, NGF-induced cells, the pro-survival Ras-ERK1/2 signaling pathway was inactivated and the pro-apoptotic JNK signaling pathway was activated. In these cells, the activation of caspase and the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) were also evident. Importantly, microarray gene expression analysis showed that more than 20 key neuronal genes that were induced by NGF were suppressed by succinyl acetone. These genes include those encoding survival motor neuron protein, synaptic vesicle protein SVOP, and neural cell adhesion molecule NCAM. These results indicate that heme is important for neuronal cell signaling and the proper functioning of neuronal cells.
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PMID:Heme deficiency suppresses the expression of key neuronal genes and causes neuronal cell death. 1595 Jul 57


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