JAC , a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis

doi:10.1073/pnas.241451198

JAC, a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis

^*Institute of Biochemistry, University of Innsbruck, Peter-Mayr-Strasse 1a, A-6020 Innsbruck, Austria; and ^‡Laboratoire de Virologie Humaine, Unité Institut National de la Santé et de la Recherche Médicale 412, 69364 Lyon Cedex 07, France

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved September 26, 2001 (received for review September 20, 2000)

Abstract

Using subtractive hybridization techniques, we have isolated a gene termed JAC that is strongly and specifically activated in avian fibroblasts transformed by the v-jun oncogene of avian sarcoma virus 17 (ASV17), but not in cells transformed by other oncogenic agents. Furthermore, JAC is highly expressed in cell lines derived from jun-induced avian fibrosarcomas. Kinetic analysis using a doxycycline-controlled conditional cell transformation system showed that expression of the 0.8-kb JAC mRNA is induced rapidly upon activation of the oncogenic v-jun allele. Nucleotide sequence analysis and transcriptional mapping revealed that the JAC gene contains two exons, with the longest ORF confined to exon 2. The deduced 68-amino acid chicken JAC protein is rich in cysteine residues and displays 37% sequence identity to mammalian high-sulfur keratin-associated proteins. The promoter region of JAC contains a consensus (5′-TGACTCA-3′) and a nonconsensus (5′-TGAGTAA-3′) AP-1 binding site in tandem, which are both specifically bound by the Gag-Jun hybrid protein encoded by ASV17. Mutational analysis revealed that the two AP-1 sites confer strong transcriptional activation by Gag-Jun in a synergistic manner. Ectopic expression of JAC in avian fibroblasts leads to anchorage-independent growth, strongly suggesting that deregulation of JAC is an essential event in jun-induced cell transformation and tumorigenesis.

jun oncogene‖signal transduction‖gene expression‖protein–DNA interaction‖transcriptional control

Footnotes

↵ † To whom reprint requests may be addressed. E-mail: markus.hartl{at}uibk.ac.at or klaus.bister{at}uibk.ac.at.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF172321, AF172322, and AF239161).
Abbreviations:

CEF,

chicken embryo fibroblasts;

QEF,

quail embryo fibroblasts;

CAT,

chloramphenicol acetyltransferase;

RSV,

Rous sarcoma virus