Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cells frequently show abnormal signaling via the mitogen activated protein kinase (MAP kinase) pathway due to increased activity of surface receptors for growth factors, or as a result of ras mutations. The development of potent anti-cancer agents that target this pathway prompts the need for analytical methods that allow pharmacodynamic monitoring of drug effects in patients during early phase clinical trial. We describe such a method, based on the activation of T-lymphocytes in undiluted peripheral blood using phorbol myristate acetate (PMA). Following rapid hypotonic lysis and formaldehyde fixation, activation of the MAP kinase pathway can then be demonstrated using phospho-specific antibodies that recognize the activated mediators MEK or ERK, followed by surface labeling with anti-CD3 to identify T-lymphocytes. This method was used to investigate the effects of a MEK inhibitor, U0126, and a new raf kinase inhibitor BAY 37-9751 in blood samples from normal donors. Dose-dependent inhibition of pERK activation was demonstrated for both agents. Furthermore, differential effects on pMEK activation allowed the molecular targets of the two inhibitors to be distinguished. In addition to monitoring drug effects in patients during treatment with inhibitors of the MAP kinase pathway, the general methodology described in this paper has the potential for wide application to the study of signal transduction at the single cell level using flow cytometry.
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PMID:Measurement of MAP kinase activation by flow cytometry using phospho-specific antibodies to MEK and ERK: potential for pharmacodynamic monitoring of signal transduction inhibitors. 1130 15

Emissions of carbonyls by motor vehicles are of concern because these species can be hazardous to human health and highly reactive in the atmosphere. The objective of this research was to measure carbonyl emission factors for California light-duty motor vehicles. Measurements were made at the entrance and exit of a San Francisco Bay area highway tunnel, in the center bore where heavy-duty trucks are not allowed. During summer 1999, approximately 100 carbonyls were identified, including saturated aliphatic aldehydes and ketones, unsaturated aliphatic carbonyls, aliphatic dicarbonyls, and aromatic carbonyls. Concentrations were measured for 32 carbonyls and were combined with NMOC, CO, and CO2 concentrations to calculate by carbon balance emission factors per unit of fuel burned. The measured carbonyl mass emitted from light-duty vehicles was 68 +/- 4 mg L(-1). Formaldehyde accounted for 45% of the measured mass emissions, acetaldehyde 12%, tolualdehydes 10%, benzaldehyde 7.2%, and acetone 5.9%. The ozone forming potential of the carbonyl emissions was dominated by formaldehyde (70%) and acetaldehyde (14%). Between 1994 and 1999, emission factors measured at the same tunnel for formaldehyde, acetaldehyde, and benzaldehyde decreased by 45-70%. Carbonyls constituted 3.9% of total NMOC mass emissions and 5.2% of NMOC reactivity. A comparison of carbonyl emissions with gasoline composition supports previous findings that aromatic aldehyde emissions are related to aromatics in gasoline. Carbonyl concentrations in liquid gasoline were also measured. Acetone and MEK were the most abundant carbonyls in unburned gasoline; eight other carbonyls were detected and quantified.
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PMID:On-road measurement of carbonyls in California light-duty vehicle emissions. 1171 32

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.
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PMID:TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. 2528 28