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Carcinogenesis. 1994 Apr;15(4):689-94.

Inhibition of gap junctional intercellular communication in Syrian hamster embryo cells by TPA, retinoic acid and DDT.

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Laboratory for Environmental and Occupational Cancer, Norwegian Radium Hospital, Oslo.


12-O-Tetradecanoylphorbol-13-acetate (TPA), trans-retinoic acid (RA) and DDT inhibit gap junctional intercellular communication in Syrian hamster embryo (SHE) cells. The inhibition is rapid and takes place within minutes. Northern blot analysis shows that SHE cells express connexin 43 and that exposure to these compounds for up to 20 h has no effect on connexin 43 mRNA level. Immune cytochemistry shows that the connexon structures in SHE cells are scattered over the cell, and not confined to the cell-cell boundaries as is the case in the rat liver epithelial cell line IAR20. RA and TPA induce the disappearance of the connexon structures in parallel to the induced inhibition of communication in SHE cells. The disappearance of the connexon spots takes place with no apparent effect on the cellular content of connexin protein measured by immunoblotting, and is probably caused by disaggregation of the connexon structures rather than disappearance or degradation of the connexin protein. DDT shows little or no apparent effect on connexin immunostaining in SHE cells, indicating a different mechanism of action. In the IAR20 cells, exposure to TPA and RA also results in loss of immunostainable connexon structures while exposure to DDT results in relocalization of the connexons away from the cell-cell borders. Immunoblotting of connexin 43 in SHE cells results in three major bands with apparent mol. wts of 40-50 kDa where the two higher mol. wt bands represent phosphorylated connexin 43 protein. Exposure of the cells to the communication inhibiting compounds results in reduction or loss of the highest mol. wt phosphorylated band, indicating a relation between a specific connexin phosphorylation and aggregation of connexin 43 protein to functional communicating gap junctions. The results suggest the presence of various post-transcriptional control mechanisms in the regulation of connexin function which are vulnerable to exogenous stimuli.

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