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)

The classical mitogen-activated protein(MAP) kinase cascade is one of the central intracellular signaling pathways that play a crucial role in cell proliferation, cell differentiation, cell transformation, and many other cellular responses. Two novel MAP kinase cascades, the SAPK/JNK cascade and the p38/MPK2 cascade, were identified, and were shown to function in various stress responses and apoptotic processes. Intracellular distribution of classical MAP kinase kinase (MAPKK/MEK) is regulated by its nuclear export signal (NES) which may function to suppress malignant cell transformation. CRM1 protein has been identified as a receptor for leucine-rich NES. CRM1 binds to CAN/NUP214, one of nucleopore proteins, which has been suggested to be involved in myeloid leukemia. Thus, the nuclear export system may be by somehow related to cancer development.
 ...
PMID:[Signal transductions by the MAP kinase cascades]. 970 53

Oxidative stress is thought to play a critical role in aging and the pathogenesis of human disease. Molecular studies of both the physiologic function of oxidants and the deleterious consequences of exposure to oxidative stress have suggested that signal transduction cascades may be targeted by oxidants. Here, we review recent studies from this laboratory examining the molecular basis for the activation of mitogen-activated protein kinases by oxidative stress and the influence of these pathways on cellular fate. We examine the association between constitutive activation of extracellular signal-regulated kinase (ERK) and cancer, and discuss how such mechanisms may contribute to oxidant-induced skin carcinogenesis. We also address the relationship between a decline in activation of this same pathway and the aged phenotype. In this regard, we review evidence that a decrease in activation of ERK by growth factor correlates with a reduced proliferative capacity in the isolated rat hepatocyte model, and we provide new data indicating that the activation of the ERK pathway in response to oxidant stimuli is also decreased with age. Further evidence demonstrates that this alteration is associated with both a reduced mitogenic response and a decline in hepatocyte cell survival in response to oxidative stress. Finally, we provide perspective on how modulations in ERK signaling may interplay with other changes in signal transduction cascades in the aging process.
 ...
PMID:Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress. 973 53

The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to define a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was defined and conserved in worms, flies and man. This was a remarkable achievement in our efforts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identification of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular effectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple effectors.
 ...
PMID:Increasing complexity of Ras signaling. 977 87

G proteins transmit signals from cell surface receptors to intracellular effectors. The intensity of the signal is governed by the rates of GTP binding (leading to subunit dissociation) and hydrolysis. Mutants that cannot hydrolyze GTP (e.g. GsalphaQ227L, Gi2alphaQ205L) are constitutively activated and can lead to cell transformation and cancer. Here we have used a genetic screen to identify intragenic suppressors of a GTPase-deficient form of the Galpha in yeast, Gpa1(Q323L). Sequencing revealed second-site mutations in three conserved residues, K54E, R327S, and L353Delta (codon deletion). Each mutation alone results in a complete loss of the beta gamma-mediated mating response in yeast, indicating a dominant-negative mode of inhibition. Likewise, the corresponding mutations in a mammalian Gi2alpha (K46E, R209S, L235Delta) lead to inhibition of Gbeta gamma-mediated mitogen-activated protein (MAP) kinase phosphorylation in cultured cells. The most potent of these beta gamma inhibitors (R209S) has no effect on Gi2alpha-mediated regulation of adenylyl cyclase. Despite its impaired ability to release beta gamma, purified recombinant Gpa1(R327S) is fully competent to bind and hydrolyze GTP. These mutants will be useful for uncoupling Gbeta gamma- and Galpha-mediated signaling events in whole cells and animals. In addition, they serve as a model for drugs that could directly inhibit G protein activity and cell transformation.
 ...
PMID:Second site suppressor mutations of a GTPase-deficient G-protein alpha-subunit. Selective inhibition of Gbeta gamma-mediated signaling. 978 51

The effect of basic fibroblast growth factor (bFGF) on human breast cancer cells was studied in vitro. Exposure to bFGF resulted in significant growth inhibition, decreased DNA synthesis, and accumulation of cells in G0-G1. The IC50 for growth inhibition in MCF-7 cells was 50 pg/ml, and it was abrogated by neutralizing antibodies against bFGF. Inhibition of growth by bFGF was predominant over the growth stimulatory effects of 17beta-estradiol, insulin, or epidermal growth factor. Binding and cross-linking studies of 125I-labeled bFGF in intact MCF-7 cells demonstrated 5.2 x 10(3) saturable bFGF binding sites per cell, a dissociation constant of 57 pm, and a Mr 142,000 (125)I-labeled bFGF cross-linked protein. Stimulation of MCF-7 cells with bFGF at concentrations which effected growth inhibition also resulted in activation of p42(mapk) (ERK2) and p44(mapk) (ERK1) mitogen-activated protein kinases. These data demonstrate that whereas bFGF inhibits the growth of several breast cancer cell lines, it concomitantly activates ERK1 and ERK2, generally considered to signal mitogenic rather than growth inhibitory responses. Whether there is association between these phenomena remains unknown.
Clin Cancer Res 1997 Jan
PMID:Basic fibroblast growth factor confers growth inhibition and mitogen-activated protein kinase activation in human breast cancer cells. 981 49

Protein kinases play a key role in intracellular signalling, participating at multiple levels along the transduction cascades that trigger mitogenic response. Because protein kinases are involved in mitogenic pathways, they are likely to play a role in the abnormal proliferation of malignant cells. In this study we compared activity of mitogen-activated protein (MAP) kinase and several renaturable kinases in homogenates of 30 surgically resected colorectal cancers and their adjacent normal tissues. Using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and membrane autophosphorylation assay on homogenates obtained from normal colon mucosa and adenocarcinoma, we identified at least four renaturable kinases (50, 55, 85, 200 kDa). Compared with adjacent tissue, in most of the cancer samples only the 85-kDa kinase exhibited a higher level of autophosphorylation activity than those in normal matched tissue (P < 0.001). Moreover, the 85-kDa kinase from nearly all cancer homogenates showed faster electrophoretic mobility than the 85-kDa kinase from normal tissue homogenates. Interestingly, the 50-kDa kinase had significantly lower autophosphorylation activity in cancer tissues than those of normal tissue (P< 0.05). To assess p42-p44 MAP kinase activity, proteins were immunoprecipitated from adjacent colon mucosa and adenocarcinoma with anti-extracellular signal-related kinase (ERK) 1/2 antibodies, and MAP kinase activity was measured using MBP as a substrate. These studies revealed that MAP kinase activity in colorectal cancer was significantly higher (P < 0.001) than that in adjacent mucosa. Thus, the constitutive activity of MAP kinase and autophosphorylation activity of 85-kDa kinase are increased, whereas the autophosphorylation activity of another kinase, 50 kDa, is decreased in colorectal adenocarcinoma. However, although signal transduction pathways are markedly altered in this cancer, neither p42/p44 MAP kinase activity nor 85-kDa autokinase activity could be correlated with the established prognostic indicators.
Br J Cancer 1998 Nov
PMID:Increased constitutive activity of mitogen-activated protein kinase and renaturable 85 kDa kinase in human-colorectal cancer. 982 70

Mutation in the ras oncogene is one of the most commonly reported genetic aberrations in human cancer. Activated ras mutants are thought to play a major role in promoting the growth and malignancy of tumor cells. Ras protein plays a central role in transmitting mitogenic signals from cell surface-to-nucleus by activating signaling pathways in response to receptor activation. Ras protein by recruiting c-Raf-1 kinase to the plasma membrane activates the mitogen-activated protein (MAP) kinase pathway. Expression of activated ras mutants in rodent fibroblast has been reported to constitutively activate the MAP kinase pathway, suggesting that constitutive activation of this pathway contributes to Ras influence on proliferation and transformation. In this study, we investigated whether stable expression of an activated Ki-Ras oncogenic mutant (G12V) in human astrocytoma cells leads to constitutive activation of the MAP kinase pathway and how this may influence cellular proliferation and signaling by epidermal growth factor (EGF) receptor. We discovered that Ki-Ras stable expression does not lead to constitutive activation of the MAP kinase pathway, rather expression of Ki-Ras plays a role in attenuating the activation of this pathway in response to EGF stimulation. Furthermore, we provide evidence that stable Ki-Ras expression attenuates the ability of EGF receptor to activate the MAP kinase pathway by interfering with the receptor ability to autophosphorylate at tyrosine residues and not by down regulating receptor expression.
 ...
PMID:Stable expression of activated Ki-Ras does not constitutively activate the mitogen-activated protein kinase pathway but attenuates epidermal growth factor receptor activation in human astrocytoma cells. 986 9

Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are potent mitogens that regulate proliferation of prostate cancer cells via autocrine and paracrine loops and promote tumor metastasis. They exert their action through binding to the corresponding cell surface receptors that initiate an intracellular phosphorylation cascade, leading to the activation of mitogen-activated protein kinases (MAPKs), which recruit transcription factors. We have studied the effects of EGF, IGF-I, and the protein kinase A (PKA) activator forskolin on the activation of p42/ extracellular signal-regulated kinase (ERK)2, which is a key kinase in mediation of growth factor-induced mitogenesis in prostate cancer cells. The activity of p42/ERK2 was determined by immune complex kinase assays and by immunoblotting using a phospho p44/p42 MAPK-specific antibody. EGF, IGF-I, and forskolin-induced PKA activity stimulate intracellular signaling pathways converging at the level of p42/ERK2. In the androgen-insensitive DU145 cell line, there is a constitutive basal p42/ ERK2 activity that is not present in androgen-sensitive LNCaP cells. Constitutive p42/ERK2 activity is abrogated by blockade of the EGF receptor. Hence, it is obviously caused by an autocrine loop involving this receptor. The effects of EGF on p42/ERK2 are potentiated by forskolin in both cell lines. The blockade of PKA by the specific inhibitor H89 attenuates this synergism. This finding is in contrast to those obtained in several other systems studied thus far, in which PKA activators inhibited MAPKs. p42/ERK2 in DU145 cells is highly responsive to IGF-I stimulation, whereas no effect of IGF-I on p42/ERK2 can be measured in LNCaP cells. Moreover, our results demonstrate that selective blockade of the EGF receptor in prostate cancer cells does not only inhibit the action of EGF, but also IGF-I-induced activation of the MAPK pathway and the interaction with the PKA pathway. In conclusion, these findings offer new possibilities for a therapeutical intervention in prostate cancer by targeting signaling pathways of growth factors and PKA.
Cancer Res 1999 Jan 01
PMID:Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines. 989 11

Pancreatic adenocarcinoma is a leading cause of adult cancer mortality in the United States. Recent studies have revealed that point mutation of the K-ras oncogene is a common event in pancreatic cancer, and oncogenesis mediated by Ras may also involve activation of Rel/nuclear factor (NF)-kappa B transcription factors. Furthermore, the c-rel member of Rel/NF-kappa B transcription factor family was first identified as a cellular homologue of the v-rel oncogene, suggesting that other members of the Rel/NF-kappa B family are potentially oncogenes. We therefore investigated the possibility that Rel/NF-kappa B transcription factors are activated in pancreatic cancer. Immunohistochemical analysis, Western blot and Northern blot analysis, electrophoretic mobility shift assays, and chloramphenicol acetyltransferase assays were performed to determine RelA activity in human pancreatic adenocarcinomas and normal tissues and nontumorigenic or tumorigenic cell lines. RelA, the p65 subunit of NF-kappa B, was constitutively activated in approximately 67% (16 of 24) of pancreatic adenocarcinomas but not in normal pancreatic tissues. Constitutive RelA activity was also detected in 9 of 11 human pancreatic tumor cell lines but not in nontumorigenic Syrian golden hamster cell lines. I kappa B alpha, a previously identified NF-kappa B-inducible gene, was overexpressed in human pancreatic tumor tissues and cell lines, and RelA activation could be inhibited by curcumin and dominant-negative mutants of I kappa B alpha, raf, and MEKK1. This is the first report demonstrating constitutive activation of RelA in nonlymphoid human cancer. These data are consistent with the possibility that RelA is constitutively activated by the upstream signaling pathway involving Ras and mitogen-activated protein kinases in pancreatic tumor cells. Constitutive RelA activity may play a key role in pancreatic tumorigenesis through activation of its downstream target genes.
Clin Cancer Res 1999 Jan
PMID:The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. 991 9

Epidermal growth factor (EGF) is produced in the ovary and influences proliferation of the malignant ovarian surface epithelium (OSE); yet its role in malignancy or in regulating the normal surface epithelium is unclear. In human OSE cells derived from primary cultures of normal tissue transfected with SV40 large T antigen (IOSE cells), EGF promoted survival but not proliferation. This survival effect was reversed by acute treatment with the phorbol ester, 12-0-tetradecanoyl-13-phorbol acetate (TPA) which alone markedly inhibited IOSE proliferation. We tested whether the activities of the mitogen-activated protein kinases (ERK1/2 and JNK1) varied in response to EGF, TPA, or combinations of these agonists and if the same treatments altered patterns of immediate early gene expression. Alone, EGF activated ERK1/2, increased and sustained levels of c-jun mRNA, but had almost no effect on JNK1 activation. Conversely, PKC activation resulted in a rapid, but transient induction of c-fos RNA and of both kinases, JNK1 and ERK2. When combined, EGF and TPA further enhanced the phosphorylation of both enzymes despite inhibiting survival. Though JNKs and ERKs are thought to transduce opposing cellular responses, in IOSE cells, robust costimulation of the JNK and ERK pathways may redirect the survival message.
 ...
PMID:Regulation of proliferation and apoptosis by epidermal growth factor and protein kinase C in human ovarian surface epithelial cells. 992 63


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