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)

In various cell types certain stresses can stimulate p38 mitogen-activated protein kinase (p38 MAPK), leading to the transcriptional activation of genes that contribute to appropriate compensatory responses. In this report the mechanism of p38-activated transcription was studied in cardiac myocytes where this MAPK is a key regulator of the cell growth and the cardiac-specific gene induction that occurs in response to potentially stressful stimuli. In the cardiac atrial natriuretic factor (ANF) gene, a promoter-proximal serum response element (SRE), which binds serum response factor (SRF), was shown to be critical for ANF induction in primary cardiac myocytes transfected with the selective p38 MAPK activator, MKK6 (Glu). This ANF SRE does not possess sequences typically required for the binding of the Ets-related ternary complex factors (TCFs), such as Elk-1, indicating that p38-mediated induction through this element may take place independently of such TCFs. Although p38 did not phosphorylate SRF in vitro, it efficiently phosphorylated ATF6, a newly discovered SRF-binding protein that is believed to serve as a co-activator of SRF-inducible transcription at SREs. Expression of an ATF6 antisense RNA blocked p38-mediated ANF induction through the ANF SRE. Moreover, when fused to the Gal4 DNA-binding domain, an N-terminal 273-amino acid fragment of ATF6 was sufficient to support trans-activation of Gal4/luciferase expression in response to p38 but not the other stress kinase, N-terminal Jun kinase (JNK); p38-activating cardiac growth promoters also stimulated ATF6 trans-activation. These results indicate that through ATF6, p38 can augment SRE-mediated transcription independently of Ets-related TCFs, representing a novel mechanism of SRF-dependent transcription by MAP kinases.
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PMID:p38 Mitogen-activated protein kinase mediates the transcriptional induction of the atrial natriuretic factor gene through a serum response element. A potential role for the transcription factor ATF6. 968 22

Lead (Pb) poisoning continues to be a significant health risk because of its pervasiveness in the environment, its known neurotoxic effects in children, and potential endogenous exposure from Pb deposited in bone. New information about mechanisms by which Pb enters cells and its organelle targets within cells are briefly reviewed. Toxic effects of Pb on the endoplasmic reticulum (ER) are considered in detail, based on recent evidence that Pb induces the expression of the gene for 78-kD glucose-regulated protein (GRP78) and other ER stress genes. GRP78 is a molecular chaperone that binds transiently to proteins traversing through the ER and facilitates their folding, assembly, and transport. Models are presented for the induction of ER stress by Pb in astrocytes, the major cell type of the central nervous system, in which Pb accumulates. A key feature of the models is disruption of GRP78 function by direct Pb binding. Possible pathways by which Pb-bound GRP78 stimulates the unfolded protein response (UPR) in the ER are discussed, specifically transduction by IRE1/ATF6 and/or IRE1/JNK. The effect of Pb binding to GRP78 in the ER is expected to be a key component for understanding mechanisms of Pb-induced ER stress gene expression.
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PMID:Lead-induced endoplasmic reticulum (ER) stress responses in the nervous system. 1258 73

Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
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PMID:[Involvement of unfolded protein responses in neurodegeneration]. 1288 50

The endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptosis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.
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PMID:[The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes]. 1557 42

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.
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PMID:Role of the unfolded protein response in cell death. 1637 48

Binding of activated forms of the proteinase inhibitor alpha2-macroglobulin (alpha2M*) to cell surface-associated GRP78 on 1-LN human prostate cancer cells causes their proliferation. We have now examined the interplay between Akt activation, regulation of apoptosis, the unfolded protein response, and activation of NF-kappaB in alpha2M*-induced proliferation of 1-LN cells. Exposure of cells to alpha2M* (50 pM) induced phosphatidylinositol 3-kinase-dependent activation of Akt by phosphorylation at Thr-308 and Ser-473 with a concomitant 60-80% increase in Akt-associated kinase activity. ERK1/2 and p38 MAPK were also activated, but there was only a marginal effect on JNK activation. Treatment of 1-LN cells with alpha2M* down-regulated apoptosis and promoted NF-kappaB activation as shown by increases of Bcl-2, p-Bad(Ser-136), p-FOXO1(Ser-253), p-GSK3beta(Ser-9), XIAP, NF-kappaB, cyclin D1, GADD45beta, p-ASK1(Ser-83), and TRAF2 in a time of incubation-dependent manner. alpha2M* treatment of 1-LN cells, however, showed no increase in the activation of caspase -3, -9, or -12. Under these conditions, we observed increased unfolded protein response signaling as evidenced by elevated levels of GRP78, IRE1alpha, XBP-1, ATF4, ATF6, p-PERK, p-eIF2alpha, and GADD34 and reduced levels of GADD153. Silencing of GRP78 gene expression by RNAi suppressed activation of Akt(Thr-308), Akt(Ser-473), and IkappaB kinase alpha kinase. The effects of alpha2M* on the NF-kappaB activation, antiapoptotic signaling, unfolded protein response signaling, and proapoptotic signaling were also reversed by this treatment. In conclusion, alpha2M* promotes cellular proliferation of 1-LN prostate cancer cells by activating MAPK and Akt-dependent signaling, down-regulating apoptotic signaling, and activating unfolded protein response signaling.
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PMID:Activation and cross-talk between Akt, NF-kappaB, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. 1654 32

Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to LC3-II. In IRE1-deficient cells or cells treated with c-Jun N-terminal kinase (JNK) inhibitor, the autophagy induced by ER stress was inhibited, indicating that the IRE1-JNK pathway is required for autophagy activation after ER stress. In contrast, PERK-deficient cells and ATF6 knockdown cells showed that autophagy was induced after ER stress in a manner similar to the wild-type cells. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.
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PMID:Autophagy is activated for cell survival after endoplasmic reticulum stress. 1703 Jun 11

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(1)-receptor-mediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive beta(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(II) immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferase-mediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. beta(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the beta(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.
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PMID:Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. 1754 81

Auto-antibodies against the beta(1)-adrenoceptors are present in 30-40% of patients with dilated cardiomyopathy. Recently, a synthetic peptide corresponding to a sequence of the second extracellular loop of the human beta(1)-adrenoceptor (beta(1)-EC(II)) has been shown to produce endoplasmic reticulum (ER) stress, myocyte apoptosis and cardiomyopathy in immunized rabbits. To study the direct cardiac effects of anti-beta(1)-EC(II) antibody in intact animals and if they are mediated via beta(1)-adrenoceptor stimulation, we administered IgG purified from beta(1)-EC(II)-immunized rabbits to recombination activating gene 2 knock-out (Rag2(-/-)) mice every 2 weeks with and without metoprolol treatment. Serial echocardiography and cardiac catheterization showed that beta(1)-EC(II) IgG reduced cardiac systolic function after 3 months. This was associated with increase in heart weight, myocyte apoptosis, activation of caspase-3, -9 and -12, and increased ER stress as evidenced by upregulation of GRP78 and CHOP and cleavage of ATF6. The Rag2(-/-) mice also exhibited increased phosphorylation of CaMKII and p38 MAPK. Metoprolol administration, which attenuated the phosphorylation of CaMKII and p38 MAPK, reduced the ER stress, caspase activation and cell death. Finally, we employed the small-interfering RNA technology to reduce caspase-12 in cultured rat cardiomyocytes. This reduced not only the increase of cleaved caspase-12 but also of the number of myocyte apoptosis produced by beta(1)-EC(II) IgG. Thus, we conclude that ER stress plays an important role in cell death and cardiac dysfunction in beta(1)-EC(II) IgG cardiomyopathy, and the effects of beta(1)-EC(II) IgG are mediated via the beta(1)-adrenergic receptor.
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PMID:Adoptive passive transfer of rabbit beta1-adrenoceptor peptide immune cardiomyopathy into the Rag2-/- mouse: participation of the ER stress. 1815 31

Disruption of endoplasmic reticulum (ER) homeostasis causes accumulation of unfolded and misfolded proteins in the ER, triggering the ER stress response, which can eventually lead to apoptosis when ER dysfunction is severe or prolonged. Here we demonstrate that human MCF-7 breast cancer cells, as well as murine NIH/3T3 fibroblasts, are rescued from ER stress-initiated apoptosis by insulin-like growth factor-I (IGF-I). IGF-I significantly augments the adaptive capacity of the ER by enhancing compensatory mechanisms such as the IRE1 alpha-, PERK- and ATF6-mediated arms of ER stress signalling. During ER stress, IGF-I stimulates translational recovery and induces expression of the key molecular chaperone protein Grp78/BiP, thereby enhancing the folding capacity of the ER and promoting recovery from ER stress. We also demonstrate that the antiapoptotic activity of IGF-I during ER stress may be mediated by a novel, as yet unidentified, signalling pathway(s). Application of signal transduction inhibitors of MEK (U1026), PI3K (LY294002 and wortmannin), JNK (SP600125), p38 (SB203580), protein kinases A and C (H-89 and staurosporine) and STAT3 (Stattic) does not prevent IGF-I-mediated protection from ER stress-induced apoptosis. Taken together, these data demonstrate that IGF-I protects against ER stress-induced apoptosis by increasing adaptive mechanisms through enhancement of ER stress-signalling pathways, thereby restoring ER homeostasis and preventing apoptosis.
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PMID:Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum. 1843 63


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