Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 have shown that the tobacco nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an agonist for -adrenergic receptors (beta-ARs) and increased DNA synthesis of human lung adenocarcinoma cells with features of bronchiolar Clara cells by binding to these receptors. Using a cell line derived from a human pulmonary adenocarcinoma with Clara cell phenotype (PACC) and immortalized human small airway epithelial cells (HPLD1), the putative cells of origin of this cancer type, our current studies have analyzed signaling initiated by binding of NNK to the beta 1-AR. NNK upregulated ERK1/2 and CREB/ATF-1 phosphorylation in a PKA-dependent manner in both cell lines. This response was further increased by transient overexpression of the beta 1-AR. Pre-exposure of cells to the selective beta 1-AR antagonist, atenolol, attenuated the stimulatory effects of NNK, suggesting the latter upregulated ERK1/2 and CREB/ATF-1 via this receptor. In vivo labeling and immunoprecipitation assays revealed that NNK phosphorylated the epidermal growth factor receptor (EGFR) at tyrosine residues, 991, 1068 and 1173, an effect inhibited by atenolol. The inhibitor of EGFR-specific tyrosine kinases, AG1478, reduced NNK ability to stimulate ERK1/2 and CREB/ATF-1. Genomic analysis of the exons 18-21 of the EGFR genes showed that no mutations were present in either gene. Collectively, our data provide evidence, for the first time, that NNK targets ERK1/2 and CREB/ATF-1 proteins via dual signaling involving beta 1-AR and EGFR pathways in PACCs and their putative cells of origin.
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PMID:NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. 1667 Oct 86

Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. In lung adenocarcinoma cells, the estrogen receptor beta (ERbeta) is the predominating form. We found that 17beta-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERbeta, an effect that involved stimulation of the adrenergic receptors beta1 (beta1AR). In transiently transfected cells, beta1AR coprecipitated with ERbeta, which increased with NNK treatment. ERbeta enhanced NNK-induced cyclic AMP accumulation as well as Galphai-mediated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 activation. Coexpression of beta1AR and ERbeta activated NNK-mediated ERK1/2 cooperatively. ERbeta gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr(308) and Ser(473), ERbeta had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERbeta stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ERbeta, the dependence on Galphai proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERbeta in the development of smoking-associated lung cancer. This novel cooperation between beta1AR and ERbeta signaling may contribute to the prominence of lung adenocarcinoma in women.
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PMID:Nongenomic beta estrogen receptors enhance beta1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells. 1763 97

Matrilysin-1 (also called matrix metalloproteinase-7) is expressed in injured lung and in cancer but not in normal epithelia. Bronchiolization of the alveoli (BOA), a potential precursor of lung cancer, is a histologically distinct type of metaplasia that is composed of cells resembling airway epithelium in the alveolar compartment. We demonstrate that there is increased expression of matrilysin-1 in human lesions and BOA in the CC10-human achaete-scute homolog-1 transgenic mouse model. Forced expression of the matrilysin-1 gene in immortalized human normal airway epithelial BEAS-2B and HPLD1 cells, which do not normally express matrilysin-1, promoted cellular migration, suggesting a functional link for BOA formation via bronchiolar cell migration. In addition, matrilysin-1 stimulated proliferation and inhibited Fas-induced apoptosis, while a knockdown by RNA interference decreased cell growth, migration, and increased sensitivity to apoptosis. Western blotting demonstrated increased levels of phospho-p38 and phospho-Erk1/2 kinases after matrilysin-1 expression. Gene expression analysis uncovered several genes that were related to cell growth, migration/movement, and death, which could potentially facilitate bronchiolization. In vivo, the formation of BOA lesions was reduced when CC10-human achaete-scute homolog-1 mice were crossed with matrilysin-1 null mice and was correlated with reduced matrilysin-1 expression in BOA. We conclude that matrilysin-1 may play an important role in the bronchiolization of alveoli by promoting proliferation, migration, and attenuation of apoptosis involving multiple genes in the MAP kinase pathway.
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PMID:Matrilysin-1 mediates bronchiolization of alveoli, a potential premalignant change in lung cancer. 1960 71