REGULATION OF C-JUN BY LUNG CARCINOGENS IN CLARA CELLS OF HAMSTERS

In vitro differentiated hamster Clara cells were used to study the eff ects of lung carcinogens on the regulation of the c-jun oncogene, Nort hern blot analysis revealed a decrease in the expression of jun transc ripts 24 h following the exposure of Clara cells to the direct acting forms of benzo[a]pyrene (BPDE) or 5-methylchrysene (5MeCDE), To deter mine 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 promote r, this activation was not observed with either 5MeCDE or the less act ive lung carcinogens BADE or 6MeCDE, Analysis of enhancer elements ide ntified 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 u pstream sequences reduced this transcriptional activation, Thus, when the complete promoter region, up to -4500, was tested, no transcriptio nal 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, possib ly 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 carcinogen s and stress inducing agents noted in various other cell systems, our findings suggest the existence of a tissue-specific regulatory respons e for c-jun.