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)

Exposure of yeast to increases in extracellular osmolarity activates the Hog1 mitogen-activated protein kinase (MAPK), which is essential for the induction of gene expression required for cell survival upon osmotic stress. Several genes are regulated in response to osmotic stress by Sko1, a transcriptional repressor of the ATF/CREB family. We show by in vivo coprecipitation and phosphorylation studies that Sko1 and Hog1 interact and that Sko1 is phosphorylated upon osmotic stress in a Hog1-dependent manner. Hog1 phosphorylates Sko1 in vitro at multiple sites within the N-terminal region. Phosphorylation of Sko1 disrupts the Sko1-Ssn6-Tup1 repressor complex, and consistently, a mutant allele of Sko1, unphosphorylatable by Hog1, exhibits less derepression than the wild type. Interestingly, Sko1 repressor activity is further enhanced in strains with high protein kinase A (PKA) activity. PKA phosphorylates Sko1 near the bZIP domain and mutation of these sites eliminates modulation of Sko1 responses to high PKA activity. Thus, Sko1 transcriptional repression is controlled directly by the Hog1 MAPK in response to stress, and this effect is further modulated by an independent signaling mechanism through the PKA pathway.
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PMID:Regulation of the Sko1 transcriptional repressor by the Hog1 MAP kinase in response to osmotic stress. 1123 Jan 35

Disruption of the RAS-to-mitogen-activated protein kinase (MAPK/ERK) signaling pathway, either directly through activating RAS gene mutations or indirectly through other genetic aberrations, plays an important role in the molecular pathogenesis of myeloid leukemias. Constitutive activation of ERK-1/2 and MEK-1/2, which elicit oncogenic transformation in fibroblasts, has recently been observed in acute myeloid leukemias (AML). In this study, the activation of the RAS-to-MAPK cascade in 14 AML and 5 chronic myeloid leukemia (CML) cell lines is examined and correlated with the effects of a panel of 9 RAS signaling inhibitors on cell viability, colony formation, cell-cycle progression, and induction of apoptosis. Activation of MEK, ERK, and the transcription factors CREB-1, ATF-1, and c-Myc is demonstrated in the majority of the cell lines (9 of 14 AML and 2 of 5 CML cell lines). Although activation of the ERK cascade did not always correlate with the presence of activating RAS mutations or BCR-Abl, it is linked to the G0/G1 and the G2/M phase of the cell cycle. In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met, FPT-2, FTI-276, and FTS), a significant growth inhibition was only observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK inhibitors U0126 (19 of 19) and PD098059 (8 of 19). Treatment of NB-4 cells with FTI-277 primarily resulted in a G2/M block, whereas treatment with FPT-3 and U0126 led to induction of apoptosis. FTI-277 revealed strong toxicity toward normal purified CD34+ cells. The results suggest differences in the mechanisms of action and support a potential therapeutic usefulness of these inhibitors in the treatment of myeloid leukemias.
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PMID:Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. 1123 26

Hepatitis B virus produces chronic infections of the liver leading to cirrhosis and hepatocellular carcinoma. The X protein of hepatitis B virus (HBx) is a multifunctional protein that can interact with p53 but can also influence a variety of signal transduction pathways within the cell. In most instances this small viral protein favors cell survival and probably initiates hepatocarcinogenesis. HBx upregulates the activity of a number of transcription factors including NF-kappa B, AP-1, CREB, and TBP. However, the majority of HBx is localized to the cytoplasm where it interacts with and stimulates protein kinases such as protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. This small viral protein can localize to the mitochondrion. HBx may act as an adaptor or kinase activator to influence signal transduction pathways. This review will attempt to analyze the involvement of HBx in signal transduction pathways during hepatitis B viral infections and hepatocellular carcinoma development.
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PMID:X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. 1132 2

The current study investigates the activation in vivo and regulation of the expression of components of the p38 mitogen-activated protein kinase (MAPK) pathway during gonadotropin-induced formation and development of the rat corpus luteum, employing a sequential PMSG/human CG (hCG) treatment paradigm. We postulated that the p38 MAPK pathway could serve to promote phosphorylation of key substrates during luteal maturation, since maturing luteal cells, thought to be cAMP-nonresponsive, nevertheless maintain critical phosphoproteins. Both p38 MAPK and its upstream activator MAPK kinase-6 (MKK6) were found to be chronically activated during the luteal maturation phase, with activation detected by 24 h post hCG and maintained through 4 days post hCG. The p38 MAPK downstream protein kinase target termed MAPK-activated protein kinase-3 (MAPKAPK-3) was newly induced at both mRNA and protein levels during luteal formation and maturation, while mRNA and protein expression of the closely related MAPKAPK-2 diminished. Two potential substrates for MAPKAPKs, the small heat shock protein HSP-27 and the cAMP regulatory element binding protein CREB, were monitored in vivo for phosphorylation. HSP-27 phosphorylation was not modulated during luteal maturation. In contrast, we observed sustained luteal-phase CREB phosphorylation in vivo, consistent with upstream MKK6/p38 MAPK activation and MAPKAPK-3 induction. MAPKAPK-3-specific immune complex kinase assays provided direct evidence that MAPKAPK-3 was in an activated state during luteal maturation in vivo. Cellular inhibitor studies indicated that an intact p38 MAPK path was required for CREB phosphorylation in a cellular model of luteinization, as treatment of luteinized granulosa cells with the p38 MAPK inhibitor SB 203580 strongly inhibited CREB phosphorylation. Transient transfection studies provided direct evidence that MAPKAPK-3 was capable of signaling to activate CREB transcriptional activity, as assessed by means of GAL4-CREB fusion protein construct coexpressed with GAL4-luciferase reporter construct. Introduction of wild-type, but not kinase-dead mutant, MAPKAPK-3 cDNA, into a mouse ovarian cell line stimulated GAL4-CREB- dependent transcriptional activity approximately 3-fold. Thus MAPKAPK-3 is indeed uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB.
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PMID:Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. 1132 54

While GAL4 fusion activators have been widely used for dissecting signal transduction pathways in transient assays, there has been surprisingly little reported on utilizing cell lines with stably integrated fusion activators. To avoid problems with the efficiency and reproducibility inherent to transient transfection, we describe here the generation and characterization of HeLa reporter cell lines, which contain a stably integrated luciferase gene responsive to stably integrated and constitutively expressed GAL4-CREB or GAL4-Elk1 fusion activators. These cell lines exhibited extremely low basal luciferase expression but robust response to various extracellular stimuli or the expression of signaling molecules that resulted in elevated MAP kinase or PKA activities. This integrated two-component reporter system allows one to focus specifically on particular signaling pathway endpoints and the altered transactivation activity of either Elk1 or CREB. With the procedures described here, many novel cell-based assays can be developed by generating new reporter cell lines with medically important but difficult-to-transfect cell types, and by using different reporter genes or different fusion transactivator genes.
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PMID:Stable luciferase reporter cell lines for signal transduction pathway readout using GAL4 fusion transactivators. 1135 49

Mitogen-activated protein kinases (MAPKs) may play crucial roles in the kainic acid (KA)-evoked excitotoxic effect and the regulation of transcription factors (e.g. c-Fos and c-Jun) in hippocampus, but their exact role in the regulation of KA-induced opioid peptides expression has not been well characterized in vivo. Therefore, we examined possible involvement of the phosphorylated form of JNK, as well as CREB, in the regulation of KA-induced proenkephalin and immediate early genes (IEGs) expression in the rat hippocampus. KA increased proenkephalin mRNA expression in rat hippocampus, which was decreased by pre-administration with cycloheximide (CHX, a protein synthesis inhibitor). KA alone increased c-fos as well as c-jun mRNA levels. CHX further enhanced KA-induced c-fos and c-jun mRNA levels. Additionally, KA increased the phosphorylation of JNK, especially JNK1, which was attenuated by CHX. CHX decreased KA-induced c-Fos protein expression. Interestingly, CHX itself increased the phosphorylation of CREB, which was abolished by KA administration. Our results suggest that the phosphorylation of JNK is involved in the up-regulation of the proenkephalin gene expression via c-Fos and c-Jun that is induced by KA in rat hippocampus. However, the phosphorylation of CREB is not associated with the up-regulation of the proenkephalin mRNA level induced by KA in the rat hippocampus.
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PMID:Possible roles of JNK pathway in the regulation of hippocampal proenkephalin and immediate early gene expression induced by kainic acid. 1135 93

Studies with invertebrates and vertebrates have strongly implicated the CREB/CRE transcriptional pathway in long-term memory (LTM) and transcriptionally-dependent L-LTP. It is hypothesized that LTM and L-LTP are both dependent upon a Ca2+ signal generated through activation of NMDA receptors. This review discusses evidence that Ca2+ signals generated through activation of NMDA receptors coactivate the Erk/MAP kinase and cAMP signal transduction pathways. It is hypothesized that activation of these two regulatory pathways increases the transcription of a family of genes through the CREB/CRE transcriptional pathway. Gene disruption studies have shown that Ca2+ activated adenylyl cyclases play a critical role in generating the cAMP signal required for LTM and L-LTP. Although cAMP may be required for several events in this complex signal transduction cascade, one of the major roles of cAMP may be to support nuclear translocation of Erk/MAP kinase in hippocampal neurons.
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PMID:Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation. 1137 99

It has been shown that UVB irradiation induces expression of COX-2 and up-regulation of COX-2 plays a functional role in UVB tumor promotion. In this study, we examined the cis-elements in the human COX-2 promoter that may be responsible for the UVB induction of COX-2. Analyses with the COX-2 promoter region revealed that the cyclic AMP responsive element near the TATA box was essential for both basal and UVB induced COX-2 expression. This was further supported by studies using a dominant negative mutant of CREB, which strongly inhibited the activity of COX-2 promoter. Electrophoretic mobility shift assays indicated that CREB and ATF-1 were the major proteins binding to the COX-2 CRE. CREB and ATF-1 were phosphorylated upon UVB treatment, and SB202190, a p38 MAPK inhibitor, decreased the phosphorylation of CREB/ATF-1 and suppressed COX-2 promoter activity. In contrast, treatment with forskolin, an activator of adenylyl cyclase, led to phosphorylation of CREB and ATF-1 and activation of COX-2 promoter. Finally, enhanced binding of phospho-CREB/ATF-1 to the COX-2 CRE was observed after UVB induction. Thus, one signaling pathway for UVB induction of human COX-2 involves activation of p38, subsequent phosphorylation of CREB/ATF-1, and activation of the COX-2 CRE through enhanced binding of phosphorylated CREB/ATF-1.
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PMID:Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes. 1152 5

Nervous system development and plasticity are regulated by neural impulse activity, but it is not well understood how the pattern of action potential firing could regulate the expression of genes responsible for long-term adaptive responses in the nervous system. Studies on mouse sensory neurons in cell cultures equipped with stimulating electrodes show that specific genes can be regulated by different patterns of action potentials, and that the temporal dynamics of intracellular signalling cascades are critical in decoding and integrating information contained in the pattern of neural impulse activity. Functional consequences include effects on neurite outgrowth, cell adhesion, synaptic plasticity and axon-glial interactions. Signalling pathways involving Ca2+, CaM KII, MAPK and CREB are particularly important in coupling action potential firing to the transcriptional regulation of both neurons and glia, and in the conversion of short-term to long-term memory. Action potentials activate multiple convergent and divergent pathways, and the complex network properties of intracellular signalling and transcriptional regulatory mechanisms contribute to spike frequency decoding.
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PMID:Regulation of gene expression by action potentials: dependence on complexity in cellular information processing. 1152 10

Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.
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PMID:Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. 1157 25


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