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Alterations in Protein Kinase C in 1,2-Dimethylhydrazine Induced Colonic Carcinogenesis¹

Department of Medicine, VA Medical Center, and University of Pittsburgh, Pittsburgh, Pennsylvania 15240

Protein kinase C activity and the profile of protein kinase C isozymes , ß, and were examined in subcellular fractions of 1,2-dimethylhydrazine induced colonic adenocarcinomas, surrounding univolved colonic mucosa and colonic mucosa from age matched control rats. Responsiveness of colonic mucosal protein kinase C to phorbol dibutyrate induced translocation of the enzyme from the soluble to the particulate cell fraction was also assessed. Although total protein kinase C and specific activities of soluble and particulate enzymes were higher in colonic mucosa of carcinogen treated rats which developed tumors than corresponding values of control mucosa, the subcellular distribution of enzyme activity was not different between uninvolved colonic mucosa of 1,2-dimethylhydrazine treated rats and colonic mucosa of age matched control rats. Thus, evidence for activation of the protein kinase C system of mucosa of the carcinogen treated rats was lacking. Exposure of colonic mucosa from control rats to phorbol dibutyrate induced a clear translocation of enzyme activity from the soluble to the particulate fraction. By contrast, no change in subcellular distribution of protein kinase C activity was noted on exposure of colonic mucosa from 1,2-dimethylhydrazine treated rats to phorbol dibutyrate. Immunoblotting of subcellular fractions of colonic mucosa from control and 1,2-dimethylhydrazine treated rats demonstrated the presence of protein kinase C , but no detectable ß and forms. Total protein kinase C activity and the specific activity of protein kinase C in soluble and particulate fractions was significantly lower in adenocarcinomas compared to uninvolved surrounding mucosa. In contrast to results obtained with colonic mucosa from control and 1,2-dimethylhydrazine treated rats, adenocarcinomas expressed predominantly the ß form of protein kinase C. The form represented less than 10% of the total detectable immunoreactivity in adenocarcinomas. The alterations in protein kinase C isoenzyme expression in tumors and loss of responsiveness of premalignant mucosa to phorbol dibutyrate may be involved in the process of malignant transformation.

¹ This work was supported by Grant CA 31608 from the National Cancer Institute, USPHS.

² To whom requests for reprints should be addressed, at the VA Medical Center, University Drive C, Pittsburgh, PA 15240.

Received 7/11/91. Accepted 2/11/92.

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