SPARC AND THROMBOSPONDIN GENES ARE REPRESSED BY THE C-JUN ONCOGENE INRAT EMBRYO FIBROBLASTS

The sequence-specific transcription factor c-Jun displays oncogenic po tential in mammalian cells either in cooperation with activated Ras in primary embryonic fibroblasts or alone in established cell lines, Alt hough pathways for signal transduction leading to activation of c-Jun proteins have been extensively studied, little is known about the even ts downstream of c-Jun stimulation, We isolated cellular genes that ar e targets of c-Jun by differential screening of a cDNA library from pr imary rat embryo fibroblasts. Two transcripts with sequences similar t o known genes were repressed following transitory expression of a c-Ju n-encoding vector, They correspond to the SPARC and thrombospondin 1 ( TS1) genes, encoding extracellular matrix proteins, These genes are ti ghtly regulated during embryogenesis and in adult tissues and are invo lved in the control of cell growth, c-Jun transitory repression of the se two genes was demonstrated both in primary cells and in FR3T3, an e stablished fibroblast cell line, The repression was also detected in F R3T3 derivatives stably transformed by c-Jun or Ras, Although c-Jun re gulation of the TS1 gene was found at the promoter level, preliminary results strongly suggest that repression of SPARC and TS1 gene express ion are mediated by a secreted factor, In contrast, expression of thes e genes was unaffected by transformation with oncogenes from DNA virus es, Our results identify new, specific, probably indirect c-Jun target genes and suggest previously unsuspected regulatory roles for SPARC a nd thrombospondin in the control of cell growth.