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)

Chronic nonneoplastic lung diseases that impair pulmonary oxygenation while increasing the levels of intrapulmonary carbon dioxide (CO2) are a documented risk factor for the development of lung cancer in smokers and nonsmokers. Using established cell lines derived from human small cell lung cancer (SCLC) and non-small cell lung carcinoma, our experiments demonstrated that elevated CO2 concentrations in the range of those found in the diseased lung selectively stimulated the proliferation of SCLC but not adenocarcinoma or squamous cell carcinoma. The proliferative response of SCLC cells involved activation of the mitogen-activated protein kinases ERK-1 and ERK-2, as well as the p70 ribosomal S6 kinase and the stimulation of an autocrine serotonergic loop. Kinase activation was unrelated to changes in intracellular pH. We concluded that CO2 is an important messenger molecule for SCLC which may contribute significantly to the high lung cancer burden observed in individuals with chronic lung disease, by the activation of kinases which play a central role as downstream effectors of many growth factor-stimulated mitogenic pathways.
 ...
PMID:Carbon dioxide, an important messenger molecule for small cell lung cancer. 931 15

Small cell lung cancer (SCLC) accounts for 25% of all lung cancers, and is almost uniformly fatal. Unlike other lung cancers, ras mutations have not been reported in SCLC, suggesting that activation of ras-associated signal transduction pathways such as the raf-MEK mitogen-activated protein kinases (MAPK) are associated with biological consequences that are unique from other cancers. The biological effects of raf activation in small cell lung cancer cells was determined by transfecting NCI-H209 or NCI-H510 SCLC cells with a gene encoding a fusion protein consisting of an oncogenic form of human Raf-1 and the hormone binding domain of the estrogen receptor (DeltaRaf-1:ER), which can be activated with estradiol. DeltaRaf-1:ER activation resulted in phosphorylation of MAPK. Activation of this pathway caused a dramatic loss of soft agar cloning ability, suppression of growth capacity, associated with cell accumulation in G1 and G2, and S phase depletion. Raf activation in these SCLC cells was accompanied by a marked induction of the cyclin-dependent kinase (cdk) inhibitor p27(kip1), and a decrease in cdk2 protein kinase activities. Each of these events can be inhibited by pretreatment with the MEK inhibitor PD098059. These data demonstrate that MAPK activation by DeltaRaf-1:ER can activate growth inhibitory pathways leading to cell cycle arrest. These data suggest that raf/MEK/ MAPK pathway activation, rather than inhibition, may be a therapeutic target in SCLC and other neuroendocrine tumors.
 ...
PMID:Activated Raf-1 causes growth arrest in human small cell lung cancer cells. 942 77

Small cell lung cancer (SCLC) is characterized by multiple genetic alterations that include inactivation of the retinoblastoma protein (Rb), the establishment of several autocrine loops including that induced by coexpression of stem cell factor (SCF) and Kit, and the ectopic expression and activation of Src family kinases. Previous studies have shown that Lck associates with, and becomes activated by, Kit after SCF stimulation of SCLC cells. In the present study, we have demonstrated that PP1, a pharmacological inhibitor of Src kinases, blocked SCF-mediated activation of mitogen-activated protein (MAP) kinase, but it also inhibited Kit activation. However, MAP kinase activation was more sensitive than Kit activation to the effects of PP1. Overexpression of Lck reduced the sensitivity of MAP kinase activation to PP1 without altering the sensitivity of Kit activation, which suggested a role for Lck in SCF-mediated MAP kinase activation. Inducible expression of a dominant negative Lck inhibited MAP kinase activation in a dose-dependent manner, which confirmed that Src family kinase activity is required for SCF-induced MAP kinase activation. The growth of cells that expressed dominant negative Lck was unaffected, however, despite the inhibition of MAP kinase. Growth was also unaffected by the inhibition of the MAP kinase pathway using PD 98059, but sensitivity to the MAP/extracellular signal-regulated kinase kinase inhibitor could be partially restored by expression of wild-type Rb. Therefore, MAP kinase activation seems to be dispensable for the growth of SCLC only in the absence of Rb expression. These data suggest that the SCF/Kit autocrine loop, through activation of Lck and subsequently MAP kinase, and the mutational inactivation of Rb contribute to the loss of G1-S phase checkpoint regulation during the pathogenesis of SCLC. Furthermore, the data demonstrate that, in established SCLC cell lines, proliferative signal transduction initiated by Kit is mediated by pathways other than the classic MAP kinase pathway.
 ...
PMID:Src family kinase activity is required for Kit-mediated mitogen-activated protein (MAP) kinase activation, however loss of functional retinoblastoma protein makes MAP kinase activation unnecessary for growth of small cell lung cancer cells. 1091 97

Expression levels of gangliosides and glycosyltransferase genes responsible for their syntheses in human lung cancer cell lines and a normal bronchial epithelial cell line were analyzed. Both non-small cell lung cancers and small cell lung cancers (SCLCs) mainly expressed G(M2) and G(M1), whereas only SCLCs expressed b-series gangliosides, such as G(D2), G(D1b), and G(T1b). Accordingly, many SCLC cell lines showed up-regulation of the G(D3) synthase gene. Consequently, we introduced G(D3) synthase cDNA into a SCLC line with low expression of b-series gangliosides and analyzed the effects of newly expressed gangliosides on tumor phenotypes. The transfectant cells expressing high levels of G(D2) and G(D3) exhibited markedly increased growth rates and strongly enhanced invasion activities. Addition of anti-G(D2) monoclonal antibodies into the culture medium of these cells resulted in the marked growth suppression of G(D2)-expressing cell lines with reduced activation levels of mitogen-activated protein kinases but not of nonexpressants, suggesting that G(D2) plays important roles in cell proliferation. Moreover, G(D2)-expressing cells treated with anti-G(D2) antibodies showed features of apoptotic cell death at 30 min after addition of antibodies, i.e., shrinkage of cytoplasm, binding of Annexin V, and staining with propidium iodide, followed by DNA fragmentation. This G(D2)-mediated apoptosis was associated with caspase-3 activation and partly inhibited by a caspase inhibitor, z-Val-Ala-Asp-fluoromethyl ketone. The finding that anti-G(D2) antibodies suppressed the cell growth and induced apoptosis of SCLC cells strongly suggested the usefulness of G(D2) as a target for the therapy of disastrous cancer, although the precise mechanisms for apoptosis remain to be clarified.
 ...
PMID:Ganglioside G(D2) in small cell lung cancer cell lines: enhancement of cell proliferation and mediation of apoptosis. 1135 51

We previously demonstrated the simultaneous induction of urokinase-type plasminogen activator and interleukin-8, a CXC chemokine, in doxorubicin-treated human NCI-H69 small cell lung cancer cells in which extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase might be involved. NCI-H69 cells expressed one of the receptor tyrosine kinases, c-Kit, and STI571 inhibited the cell growth and stem cell factor-induced phosphorylation of c-Kit. We therefore investigated the effects of STI571 on the expression of urokinase-type plasminogen activator and interleukin-8 in NCI-H69 cells. Microarray analysis revealed the gene induction of not only urokinase-type plasminogen activator and interleukin-8, but also early growth response-1 in STI571-treated cells. Treatment with STI571 resulted in the induction of phosphorylation of all three mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and stress-activated protein kinase/c-jun N-terminal protein kinase. U0126, an inhibitor against extracellular signal-regulated kinase 1/2, however, only inhibited the STI571-induced interleukin-8 accumulation. Urokinase-type plasminogen activator and interleukin-8 are important biological factors in tumor cell regulation; STI571 may therefore influence many aspects of tumor cell biology through inducing urokinase-type plasminogen activator and interleukin-8, in which the induction of early growth response-1 expression and extracellular signal-regulated kinase 1/2 phosphorylation might be involved.
 ...
PMID:Induction of urokinase-type plasminogen activator, interleukin-8 and early growth response-1 by STI571 through activating mitogen activated protein kinase in human small cell lung cancer cells. 1758 16

The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling.
 ...
PMID:Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. 2807 2