Mouse 3T3-L1 cell variants unable to respond to mitogenic stimulation of dihydroteleocidin B: genetic evidence for the synergism of tumor promoters with growth factors.
Dihydroteleocidin B, an indole alkaloid tumor promoter, stimulates confluent, quiescent mouse 3T3-L1 fibroblasts to initiate DNA synthesis and undergo cell division. Using a mitotic shakeoff technique, we have isolated 12 clones of genetic variants which are unable to respond to the mitogenic stimulation of dihydroteleocidin B from a total of 12 million cells. Biochemical characterization of these nonresponsive variants to dihydroteleocidin B revealed that there is no change in the ability to bind [3H]phorbol dibutyrate, the activity of protein kinase C, and the turnover of phosphatidylinositol. The evidence indicates that nonresponsiveness to dihydroteleocidin B is caused by several different lesions, including defects in receptors for insulin or epidermal growth factor and in the postreceptor mechanisms. The evidence also suggests that mitogenic signal transfer via the epidermal growth factor receptor system appears to share a common step with dihydroteleocidin B whereas the signal transfer for insulin seems separate from these. These results suggest that phosphatidylinositol turnover followed by protein kinase C activation alone is not sufficient for mitogenic stimulation and that the coordination of the protein kinase C system with the receptor systems for growth factors may be necessary for "full" mitogenic response.
D000818:Animals; D002273:Carcinogens; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004357:Drug Synergism; D066246:ErbB Receptors; D006657:Histones / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008235:Lyngbya Toxins / Q000494:pharmacology*; D051379:Mice; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000032:analysis; D011972:Receptor, Insulin / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis*; D014316:Tritium
D002273:Carcinogens; D006657:Histones; D007328:Insulin; D008235:Lyngbya Toxins; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; D014316:Tritium; D015240:Phorbol 12,13-Dibutyrate; D004247:DNA; C022229:dihydroteleocidin B; D066246:ErbB Receptors; D011972:Receptor, Insulin; D011493:Protein Kinase C