A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1.
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.
Tindberg
Niclas
N
Institute for Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, S-171 77 Stockholm, Sweden. nictin@ki.se
Bengtsson
Inger
I
Hu
Yin
Y
D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D007438:Introns / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics / Q000502:physiology; D017422:Sequence Analysis, DNA; D014162:Transfection
D008070:Lipopolysaccharides; D046911:Macromolecular Substances; D016755:Proto-Oncogene Proteins c-jun; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases