The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.
In cooperation with an activated ras oncogene, the site-dependent AP-1 transcription factor c-Jun transforms primary rat embryo fibroblasts (REF). Although signal transduction pathways leading to activation of c-Jun proteins have been extensively studied, little is known about c-Jun cellular targets. We identified c-Jun-upregulated cDNA clones homologous to the tenascin-C gene by differential screening of a cDNA library from REF. This tightly regulated gene encodes a rare extracellular matrix protein involved in cell attachment and migration and in the control of cell growth. Transient overexpression of c-Jun induced tenascin-C expression in primary REF and in FR3T3, an established fibroblast cell line. Surprisingly, tenascin-C synthesis was repressed after stable transformation by c-Jun compared to that in the nontransformed parental cells. As assessed by using the tenascin-C (-220 to +79) promoter fragment cloned in a reporter construct, the c-Jun-induced transient activation is mediated by two binding sites: one GCN4/AP-1-like site, at position -146, and one NF-kappaB site, at position -210. Furthermore, as demonstrated by gel shift experiments and cotransfections of the reporter plasmid and expression vectors encoding the p65 subunit of NF-kappaB and c-Jun, the two transcription factors bind and synergistically transactivate the tenascin-C promoter. We previously described two other extracellular matrix proteins, SPARC and thrombospondin-1, as c-Jun targets. Thus, our results strongly suggest that the regulation of the extracellular matrix composition plays a central role in c-Jun-induced transformation.
Mettouchi
A
A
Institut de Recherche sur le Cancer, CNRS UPR9079, Villejuif, France.
Cabon
F
F
Montreau
N
N
Dejong
V
V
Vernier
P
P
Gherzi
R
R
Mercier
G
G
Binétruy
B
B
D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000378:metabolism; D005784:Gene Amplification; D005786:Gene Expression Regulation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000494:pharmacology*; D051381:Rats; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics; D019699:Thrombospondins; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D015676:Osteonectin; D016755:Proto-Oncogene Proteins c-jun; D019063:Tenascin; D019699:Thrombospondins; D018808:Transcription Factor AP-1; D016283:Proto-Oncogene Proteins p21(ras)