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Molecular and Cellular Biology, December 1998, p. 7020-7029, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Transcription Factor ATF2 Cooperates with v-Jun To Promote Growth Factor-Independent Proliferation In Vitro and Tumor Formation In Vivo

Stéphanie Huguier,1 Joël Baguet,1 Sandrine Perez,1 Hans van Dam,2 and Marc Castellazzi1,*

Unité de Virologie Humaine, Institut National de la Santé et de la Recherche Médicale (INSERM-U412), Ecole Normale Supérieure, 69364 Lyon Cedex 07, France,1 and Sylvius Laboratories, Leiden University Medical Center, 2300 RA Leiden, The Netherlands2

Received 18 May 1998/Returned for modification 1 July 1998/Accepted 4 September 1998

ATF2 belongs to the bZIP family of transcription factors and controls gene expression via 8-bp ATF/CREB motifs either as a homodimer or as a heterodimer---for instance, with Jun---but has never been shown to be directly involved in oncogenesis. Experiments were designed to evaluate a possible role of ATF2 in oncogenesis in chick embryo fibroblasts (CEFs) in the presence or absence of v-Jun. We found that (i) forced expression of ATF2 cannot alone cause transformation, (ii) overexpression of ATF2 plus v-Jun specifically stimulates v-Jun-induced growth in medium with a reduced amount of serum, and (iii) the efficiency of low-serum growth correlates with the activity of a Jun-ATF2-dependent model promoter in stably transformed CEFs. Analysis of ATF2 and Jun dimerization mutants showed that the growth-stimulatory effect of ATF2 is likely to be mediated by v-Jun-ATF2 heterodimers since (i) v-Jun-m1, a mutant with enhanced affinity for ATF2, induces growth in low-serum medium much more efficiently than v-Jun, when expressed alone or in combination with ATF2; and (ii) ATF2/fos, a mutant that efficiently binds to v-Jun but is unable to form stable homodimers, shows enhanced oncogenic cooperation with v-Jun. In addition, we examined the role of ATF2 in tumor formation by subcutaneous injection of CEFs into chickens. In contrast to v-Jun, v-Jun-m1 gave rise to numerous fibrosarcomas while coexpression of ATF2 and v-Jun-m1 led to a dramatic development of fibrosarcomas visible within 1 week. Together these data demonstrate that overexpressed ATF2 potentiates the ability of v-Jun-transformed CEFs to grow in low-serum medium in vitro and contributes to the formation of tumors in vivo.

* Corresponding author. Mailing address: INSERM-U412, 46 Allée d'Italie, 69364 Lyon Cedex 07, France. Phone: 33-(0)4-7272-8165. Fax: 33-(0)4-7272-8696. E-mail: marc.castellazzi{at}ens-lyon.fr.

Molecular and Cellular Biology, December 1998, p. 7020-7029, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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