Role of protein kinase C in regulation of gene expression and relevance to tumor promotion.
The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) has highly pleiotropic effects on cells in culture and on tissues in vivo, including effects on protein kinase C (PKC) activation and gene expression. In order to determine the mechanism of activation of gene transcription by TPA, DNA sequences whose transcription is modulated in cells undergoing a mitogenic response to TPA were isolated by differential screening of a cDNA library from TPA-treated cells. TPA-S1 corresponds to an mRNA species whose abundance is increased within 1 hr of exposure of quiescent C3H 10T1/2 mouse embryo fibroblasts. TPA-R1 corresponds to an mRNA species whose abundance is decreased in TPA-treated cells. The induction of TPA-S1 is blocked by actinomycin D and is specific for phorbol esters with tumor-promoting activity. The transcription of this sequence is not induced by cycloheximide, nor is there an enhancement of the TPA response. Several lines of evidence demonstrate that PKC activation plays a critical role in the regulation of TPA-S1 expression. The nucleotide and predicted amino acid sequence of TPA-S1 exhibits homology with sequences representing a peptide with erythroid-potentiating activity, a metalloproteinase inhibitor protein, and a murine protein with beta-interferon-like activity. The role of TPA-S1 in tumor promotion is suggested by the expression of this sequence in mouse skin carcinomas induced by dimethyl-benzanthracene-TPA treatment, but not in papillomas or in control tissue. The consideration of signal transduction pathways may be useful in the design of short-term risk assessment assays for agents that act as tumor promoters.
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012306:Risk; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D011506:Proteins; D012313:RNA; D004247:DNA; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate