c-myc Gene-induced Alterations in Protein Kinase C Expression: A Possible Mechanism Facilitating myc-ras Gene Complementation

The mechanism(s) by which the c-myc nuclear protein and the mem brane-associated ras protein interact to mediate phenotypic changes is unknown. We now find that c-mcy gene expression is associated with alterations in the principal signal transduction pathway through which the ras protein is thought to function. We studied the transcript and protein expression of protein kinase C (PKC) isoforms in a culture line of human small cell lung cancer cells (NCI H209) in which expression of inserted c-myc and ila-ras genes together, but not alone, causes a transition to a large cell phenotype. In control H209 cells, at the transcript and cell membrane protein levels, PKC-a is the dominant PKC species. In this cell line, the expression of an exogenous c-myc gene, but not of a viral I la-ra.v gene, causes a 5- to 10-fold increase in the PKC-/Õisoform transcript and protein. The insertion of ras into the exogenous mycexpressing 209 cells, in addition to causing phenotypic transition, results in the translocation of the PKC-/)' protein from the cytosol to the mem brane fraction and a decrease in membrane-associated PKC-a. Concom itant with these changes, the increased PKC isoform transcript levels induced by myc alone are completely reversed. These observations sug gest that a complex set of PKC transcript and protein alterations, most prominently involving an increased PKC-/? protein level in the cell mem brane, a decrease in PKC-a protein, and a decrease in all PKC isoform transcripts, may represent a fundamental event(s) for c-myc collaboration with Ila-ras to alter cell phenotype.