Transcription factor ATF2 cooperates with v-Jun to promote growth factor-independent proliferation in vitro and tumor formation in vivo.
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.
Huguier
S
S
Unité de Virologie Humaine, Institut National de la Santé et de la Recherche Médicale (INSERM-U412), Ecole Normale Supérieure, 69364 Lyon Cedex 07, France.
Baguet
J
J
Perez
S
S
van Dam
H
H
Castellazzi
M
M
D051698:Activating Transcription Factor 2; D000818:Animals; D002455:Cell Division / Q000235:genetics*; D002642:Chick Embryo; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006133:Growth Substances / Q000235:genetics*; D016350:Leucine Zippers / Q000502:physiology; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics*; D016759:Oncogene Protein p65(gag-jun) / Q000235:genetics*; D015513:Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D006133:Growth Substances; D016759:Oncogene Protein p65(gag-jun); D015513:Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors