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)

Adenosine deaminase (ADA) regulates cellular levels of adenosine and deoxyadenosine, and 17beta-estradiol (E(2)) induces ADA mRNA in MCF-7 human breast cancer cells. IGF-I also induces ADA gene expression in these cells, and induction of this response through IGF activation of estrogen receptor alpha (ERalpha) was further investigated. IGF and other polypeptide growth factors induce reporter gene expression in MCF-7 cells cotransfected with ERalpha expression plasmid and pADA211, a construct containing the -211 to +11 region of the ADA gene promoter which is required for high basal and E(2)-inducible activity. Deletion analysis of this promoter demonstrates that IGF activates ERalpha/Sp1 interactions with multiple GC-rich sites in the promoter and this response is abrogated in cells transfected with ERalpha containing mutations at Ser(118) or Ser(163). IGF induces both MAPK (mitogen-activated protein kinase) and PI3-K (phosphatidylinositol-3-kinase) phosphorylation cascades in MCF-7 cells; however, using a series of inhibitors and dominant negative constructs, our results show that induction of ADA by IGF activation of ERalpha/Sp1 is dependent on the MAPK signaling pathway.
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PMID:Activation of adenosine deaminase in MCF-7 cells through IGF-estrogen receptor alpha crosstalk. 1135 58

We have previously shown that hypertonic stress (HS) can suppress chemoattractant-induced neutrophil responses via cyclic adenosine monophosphate and enhance these responses through p38 mitogen-activated protein kinase (MAPK) activation. The underlying mechanisms are unknown. Here, we report that HS dose-dependently releases adenosine 5'-triphosphate (ATP) from neutrophils and that extracellular ATP is rapidly converted to adenosine or activates p38 MAPK and enhances N-formyl-methionyl-leucyl-phenylalanine-induced superoxide formation. In contrast, adenosine suppresses superoxide formation. Adenosine deaminase treatment abolished the suppressive effect of HS, indicating that HS inhibits neutrophils through adenosine generation. Neutrophils express mRNA, encoding all known P1 adenosine receptors (A1, A2a, A2b, and A3) and the nucleotide receptors P2Y2, P2Y4, P2Y6, P2Y11, and P2X7. A2 receptor agonists mimicked the suppressive effects of HS; the A2 receptor antagonists 8-(p-sulfophenyl)theophylline, 3,7-dimethyl-1-(2-propynyl)xanthine, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, and 3-propylxanthine, but not A1 and A3 receptor antagonists, decreased the suppressive effect of HS, indicating that HS suppresses neutrophils via A2 receptor activation. Antagonists of P2 receptors counteracted the enhancing effects of ATP, suggesting that HS costimulates neutrophils by means of P2 receptor activation. We conclude that hypertonic stress regulates neutrophil function via a single molecule (ATP) and its metabolite (adenosine), using positive- and negative-feedback mechanisms through the activation of P2 and A2 receptors, respectively.
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PMID:A putative osmoreceptor system that controls neutrophil function through the release of ATP, its conversion to adenosine, and activation of A2 adenosine and P2 receptors. 1510 62

Malignant melanoma is the most deadly type of skin cancer. The lack of effective pharmacological approaches for this tumour can be related to the incomplete understanding of the pathophysiological mechanisms involved in melanoma cell proliferation. Adenosine has growth-promoting and growth inhibitory effects on tumour cells. We aimed to investigate effects of adenosine and its metabolic product, inosine, on human C32 melanoma cells and the signalling pathways involved. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and bromodeoxyuridine (BrdU) proliferation assays were used to evaluate adenosine, adenosine deaminase and inosine effects, in the absence or presence of adenosine receptor (AR), A3 AR and P2Y1 R antagonists and PLC, PKC, MEK1/2 and PI3K inhibitors. ERK1/2 levels were determined using an ELISA kit. Adenosine and inosine levels were quantified using an enzyme-coupled assay. Adenosine caused cell proliferation through AR activation. Adenosine deaminase increased inosine levels (nanomolar concentrations) on the extracellular space, in a time-dependent manner, inducing proliferation through A3 AR activation. Micromolar concentrations of inosine enhanced proliferation through A3 AR activation, causing an increase in ERK1/2 levels, and P2Y1 R activation via ENT-dependent mechanisms. We propose the simultaneous activation of PLC-PKC-MEK1/2-ERK1/2 and PI3K pathways as the main mechanism responsible for the proliferative effect elicited by inosine and its significant role in melanoma cancer progression.
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PMID:Inosine strongly enhances proliferation of human C32 melanoma cells through PLC-PKC-MEK1/2-ERK1/2 and PI3K pathways. 2490 96