Elevated binding to URE/PEBP2 during the late stages of NNK and benzo[a]pyrene-induced carcinogenesis in A/J mice

To provide better understanding about the alterations in transcription factor activities during the promotion and progression stages of lung carcinogenesis we have utilized the A/J mice lung tumor model in which two potent lung carcinogens, 4-(methyl-nitrosamino) -1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP), were co-administered. Nuclear proteins prepared from lung, brain, kidney, liver and colon of the A/J mice, 19 weeks after the last carcinogen administration, as well as from their respective non-treated controls, were tested for their binding to polyoma enhancer binding protein 2 (PEBP2) target sequence and UV-responsive element (URE). PEBP2 represents a newly identified family of transcription factors that was shown to play a role in cellular differentiation and transformation. URE is similar to CRE and AP1 target sequences, to which the members of ATF/AP1 transcriptional factors family bind. We demonstrate here that there is a marked increase in binding to both PEBP2 and URE sequences in lung, liver, kidney and brain of the treated mice. Such binding appears to be dependent on the mode of carcinogen administration as it was better noticed in the intragastric injected group than in the intraperitoneal group. Taken together, our findings suggest that increased binding to the URE and to PEBP2 target sequence reflects changes in transcriptional activities which occur at late stages of lung carcinogenesis in a fashion which appear to depend on mode of carcinogen administration.