Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome P450 2E1 (CYP2E1) is highly inducible in a subset of astrocytes in vivo following ischemic or mechanical injury and in vitro by lipopolysaccharide (LPS) or interleukin-1beta. We have studied the mechanism of induction, and found that transcriptional activation of CYP2E1 occurred within 3 h, and CYP2E1 dependent catalytic activity was induced more than 4-fold within 5 h. The induction was sensitive to several tyrosine kinase inhibitors, and was further modulated by inhibitors of p38 MAP kinase. MAP kinase kinase-3 (MKK3) was phosphorylated in response to LPS, and expression of constitutively active MKK3, but not the MAP kinase kinases MEKK1 or MKK1, activated CYP2E1. Transcriptional activation was mediated through a C/EBPbeta and -delta binding element situated at -486/-474, and appeared to involve activation of prebound factors as well as recruitment of newly synthesized C/EBPbeta and -delta. It is thus suggested that LPS induces MKK3 activation in astrocytes, which in turn stimulates a C/EBPbeta and -delta binding element to mediate transcriptional activation of CYP2E1.
 ...
PMID:Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta. 1467 Sep 49

Cytochrome P450 2E1 (CYP2E1) exhibits a pronounced oxidase activity that may mediate apoptotic injury in glial cells as well as hepatocytes. Strict regulation of CYP2E1 and it's activity is therefore thought to be crucial. We have studied CYP2E1 transcriptional regulation in primary cortical glial cells and have identified a novel repressor element at +1452/+1460 in intron 2 of the rat CYP2E1 gene. The element very potently repressed CYP2E1 and SV40 promoters and consisted of the non-palindromic core sequence 5'-TTCCACTCA-3'. Jun proteins were found to interact with the site. The protein complexes were also found to contain an as yet unidentified protein of approximately 60 kDa, probably with DNA binding properties similar to G-box binding factors found in, e.g. Arabidopsis thaliana. Stimulation with lipopolysaccharide, or overexpression of the mitogen-activated protein kinase kinase kinase, MEKK-1, further deepened the repression in primary cortical glial cells. It is suggested that this novel Jun binding repressor helps to control basal expression levels of CYP2E1, and modulates the response to inflammatory factors. Future in vivo experiments will, however, be required for a full appreciation of the role of this repressor in the complex regulation of CYP2E1 during inflammatory conditions.
 ...
PMID:A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1. 1518 36