A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion.
Okadaic acid (OA) is a prototypical non-phorbol ester skin tumor-promoting agent that works by inhibiting protein phosphatases, leading to an increase in protein phosphorylation. Increased protein phosphorylation can lead to stimulated signaling through various signal transduction pathways. One or more of the pathways affected by OA leads to increased signaling via the activator protein 1 (AP-1) transcription factor. Because AP-1 signaling has been shown to be required for skin tumor promotion by phorbol ester, studies were undertaken to determine whether AP-1 signaling is also required for 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/OA-promoted skin tumorigenesis. Transgenic mice expressing a dominant negative c-jun (TAM-67) controlled by the keratin 14 promoter in ICR mice were used to determine the effects of OA on AP-1 signaling. By crossing the TAM-67 mice with mice expressing an AP-1-responsive luciferase, it was shown that TAM-67 decreases AP-1 activation in response to OA treatment by 95%. After 7,12-dimethylbenz(a)anthracene initiation, the TAM-67 mice and nontransgenic littermates were promoted with twice weekly applications of OA. These experiments showed that TAM-67 expression decreased tumor multiplicity by 90%. Additional experiments with TAM-67 mice showed that the hyperplastic response to OA is not impaired in these mice, nor were there differences in OA-induced transcription of various genes known to be AP-1 responsive under other conditions. This result suggests that only a subset of AP-1-regulated genes is targeted by TAM-67 when it prevents tumor promotion by OA. A determination of the mechanism by which TAM-67 can block tumor promotion without affecting hyperplasia will be important.
Thompson
Eric J
EJ
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85724, USA.
MacGowan
Jacalyn
J
Young
Matthew R
MR
Colburn
Nancy
N
Bowden
G Tim
GT
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D019319:Okadaic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology
D002273:Carcinogens; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D019319:Okadaic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D019278:Matrix Metalloproteinase 3