Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun

Abstract

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-1α) 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 (∼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.