Gene regulation and genetic susceptibility to neoplastic transformation: AP-1 and p80 expression in JB6 cells.
The mouse epidermal JB6 cell system consists of clonal genetic variants that are sensitive (P+) or resistant (P-) to the promotion of neoplastic transformation by phorbol esters and other tumor-promoting agents. P+ cells display AP-1-dependent phorbol-ester-inducible transactivation of gene expression, whereas P- cells have a defect in transactivation. Transfection of promotion sensitivity gene pro-1 into P- cells reconstituted both P+ phenotype and AP-1-dependent phorbol-ester-inducible transactivation. P- and P+ cells exhibited induction of c-jun and c-fos messenger RNA levels by phorbol ester, but P- cells had significantly lower basal and induced levels of jun mRNA than P+ cells. Basal and induced levels of c-jun protein were significantly lower in P- cells as well. Differences in levels the 80-kDa pI 4.5 protein p80 were also observed in JB6 cells as a function of preneoplastic progression; high levels of p80 protein and mRNA were observed in P- cells, intermediate levels in P+ cells, and negligible levels were observed in transformed derivatives of JB6 cells. Phorbol ester treatment induced phosphorylation but not synthesis of p80. These data are consistent with the hypotheses that AP-1 is required in the signal transduction pathway for promotion of neoplastic transformation by tumor promoter, that pro genes may control AP-1 activity, that threshold levels of Jun mRNA and protein may play a role in transactivation and promotion sensitivity, and that the p80 protein in JB6 cells may behave in vivo as a suppressor of cellular transformation.
Bernstein
L R
LR
Cell Biology Section, National Cancer Institute-FCRDC, Frederick, MD 21702.
Ben-Ari
E T
ET
Simek
S L
SL
Colburn
N H
NH
D000595:Amino Acid Sequence; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D004742:Enhancer Elements, Genetic; D000078404:Epidermal Cells; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects
D002273:Carcinogens; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; C036987:protein p80