Regulation of c-jun by lung carcinogens in Clara cells of hamsters.
In vitro differentiated hamster Clara cells were used to study the effects of lung carcinogens on the regulation of the c-jun oncogene. Northern blot analysis revealed a decrease in the expression of jun transcripts 24 h following the exposure of Clara cells to the direct acting forms of benzo[a]pyrene (BPDE*) or 5-methylchrysene (5MeCDE). To determine whether this decrease was mediated at the transcriptional level, we have used CAT reporter constructs driven by nested deletions of the 5' non-coding regulatory region of the c-jun oncogene. While BPDE was capable of activating certain regulatory domains of the c-jun promoter, this activation was not observed with either 5MeCDE or the less active lung carcinogens BADE or 6MeCDE. Analysis of enhancer elements identified the SP1 target site as a strong silencer after BPDE treatment. While positive regulatory element(s) mediating activation of c-jun by BPDE were localized within the promoter region up to -1639, further upstream sequences reduced this transcriptional activation. Thus, when the complete promoter region, up to -4500, was tested, no transcriptional activation was noted following BPDE treatment. These observations suggest that the regulation of c-jun in Clara cells exposed to potent lung carcinogens is mediated at the post-transcriptional level, possibly by reducing the stability and, in turn, the half life of c-jun mRNA. Overall, in contrast to the response of c-jun to numerous carcinogens and stress inducing agents noted in various other cell systems, our findings suggest the existence of a tissue-specific regulatory response for c-jun.
Dolan
L R
LR
American Health Foundation, Valhalla, NY 10595.
Rutberg
S E
SE
Amin
S
S
Emura
M
M
Mohr
U
U
Kraft
A
A
Yokoyama
K
K
Ronai
Z
Z
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002911:Chrysenes / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008647:Mesocricetus; D008969:Molecular Sequence Data; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D002911:Chrysenes; D011993:Recombinant Fusion Proteins; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C026832:3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene; C037783:1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; C050280:1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene