We have used chicken
cDNA microarrays to investigate gene-expression changes induced during transformation of chick embryo fibroblasts (CEF) by the viral Jun
oncoprotein encoded by ASV17. This analysis reveals that v-Jun induces increases and decreases of varying magnitude in the expression of genes involved in diverse cellular functions, most of which have not been detected in previous screens for putative v-Jun targets. In all, 27 individual genes were identified, whose expression is increased threefold or more in v-Jun-transformed cells, including genes involved in energy generation,
protein synthesis, and gene transcription. Interestingly, this group includes the
hypoxia-inducible factor-1 alpha (Hif-1alpha)
transcription factor and the glycolytic
enzyme enolase, suggesting that adaptation to
hypoxia could play a role in
tumorigenesis by v-Jun. We also identified 32 genes whose expression is decreased threefold or more, including chaperones, components of the cytoskeleton, and, unexpectedly, DNA replication factors. The gene whose expression is upregulated most dramatically (approximately 100-fold) encodes Autotaxin (ATX), a secreted
tumor motility-promoting factor with
lysophospholipase D activity. Strikingly, v-Jun-transformed CEF secrete catalytically active ATX and chemotactic activity, which can be detected in
conditioned medium. ATX is not detectably expressed in normal CEF or CEF transformed by the v-Src or v-Myc
oncoproteins, indicating that induction of this putative autocrine/paracrine factor is a specific consequence of cell transformation by v-Jun. ATX has been implicated in both angiogenesis and invasion, and could therefore play an important role in
tumorigenesis by v-Jun in vivo.