v-Jun represses c-jun proto-oncogene expression in vivo through a 12-O-tetradecanoylphorbol-13-acetate-responsive element in the proximal gene promoter.
c-jun proto-oncogene expression is extinguished in cells transformed by v-Jun; however, the mechanistic basis of this phenomenon has not been elucidated. c-jun mRNA levels are greatly reduced in v-Jun-transformed cells, and we show that this reduction is associated with a similar decrease in the rate of c-jun transcription. Transcriptional down-regulation was also evident in functional assays in which the c-jun gene promoter was approximately 10-fold less active in v-Jun-transformed cells than it was in normal cells. This reduction was largely attributable to a conserved 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE)-like motif at position -72 (the proximal junTRE) that was essential for efficient basal expression in normal cells but that conferred little, if any, detectable transcriptional activity in v-Jun-transformed cells. DNA-binding analysis showed that this element was recognized by a mixture of c-Jun/Fra and cyclic AMP-responsive element-binding protein/activating transcription factor-like complexes in normal cells but that v-Jun/Fra heterodimers predominated in v-Jun-transformed cells. Furthermore, ectopic expression of v-Jun repressed c-jun promoter activity in normal cells through the proximal junTRE. Thus, the deficit in transcription mediated by the junTRE correlates with and is most likely attributable to binding of v-Jun to this element in vivo. We also find that the c-jun promoter is refractory to induction via the stress-activated protein kinase/c-jun NH2-terminal kinase pathway in v-Jun-transformed cells, suggesting that v-Jun interferes with signal-regulated gene expression. Therefore, c-jun is an example of a cellular gene, the transcription of which is regulated negatively by v-Jun in vivo.
Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Bearsden, Glasgow, United Kingdom.
S
S
Hussain
A
A
Kilbey
D A
DA
Gillespie
D051696:Activating Transcription Factors; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002461:Cell Line, Transformed; D002642:Chick Embryo; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D005347:Fibroblasts; D005786:Gene Expression Regulation; D016758:Genes, jun; D048031:JNK Mitogen-Activated Protein Kinases; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D018006:Myogenic Regulatory Factors; D016759:Oncogene Protein p65(gag-jun) / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099169:Fos-Related Antigen 1
D051696:Activating Transcription Factors; D001798:Blood Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D018006:Myogenic Regulatory Factors; D016759:Oncogene Protein p65(gag-jun); D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1