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Transcription Factor ATF3 Partially Transforms Chick Embryo Fibroblasts by Promoting Growth Factor-Independent Proliferation

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Transcription Factor ATF3 Partially Transforms Chick Embryo Fibroblasts by Promoting Growth Factor-Independent Proliferation Oncogene (2001) 20, 1135 ± 1141 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc SHORT REPORT Transcription factor ATF3 partially transforms chick embryo ®broblasts by promoting growth factor-independent proliferation Sandrine Perez1, Emmanuel Vial1, Hans van Dam2 and Marc Castellazzi*,1 1Unite de Virologie Humaine, Institut National de la Sante et de la Recherche MeÂdicale (INSERM-U412), Ecole Normale SupeÂrieure, 46 alleÂe d'Italie, 69364 Lyon Cedex 07, France; 2Department of Molecular Cell Biology, Leiden University Medical Center, Sylvius Laboratories, 2300 RA Leiden, The Netherlands Activating Transcription Factor 3 (ATF3) is a member levels and activities of the various Jun, Fos, ATF and of the bZip family of transcription factors. Previous Maf monomers present. AP1 complexes mediate studies in mammalian cells suggested that like other cellular responses to a wide variety of extracellular bZip family members e.g. Jun and Fos, ATF3 might play stimuli, including growth factors, cytokines and agents a role in the control of cell proliferation and participate inducing genotoxic stress (Angel and Karin, 1991; in oncogenic transformation. To investigate this putative Karin et al., 1997; Wisdom, 1999). ATF3 function directly, the rat ATF3 protein was Comparison of the ATF3 sequences from rat (Hsu et compared with v-Jun for its ability to transform primary al., 1991), mouse (Drysdale et al., 1996) and man (Hai cultures of chick embryo ®broblasts (CEFs). Like CEFs et al., 1989) shows that the gene displays a high degree accumulating v-Jun, CEFs accumulating the ATF3 of conservation in vertebrates. Recently, an ATF3 protein displayed a typical, fusiform morphology, homolog has also been isolated in the Japanese associated with an enhanced capacity to grow in medium puer®sh Fugu rubripes (Trower et al., 1996; Venkatesh with reduced amount of serum. However, in contrast to et al., 2000). In rodents, ATF3 is expressed at relatively v-Jun-transformed CEFs, the ATF3 overexpressing cells low level in most cell types (Freeman et al., 1998) with could not promote colony formation from single cells in the exception of skeletal muscle, intestine, and stomach agar. Partial transformation induced by ATF3 was found tissues (Hsu et al., 1991). At present, most of the to be associated with repression of multiple cellular genes signalling pathways that activate ATF3, speci®c that are also down-regulated by v-Jun, including those functions of the various ATF3-containing dimers, and coding for the extracellular components ®bronectin, speci®c ATF3 target genes remain to be elucidated decorin, thrombospondin 2, and the pro-apoptotic protein (Hai et al., 1999). Par-4. These data demonstrate that, at least in primary ATF3 shares several properties with the oncoprotein avian cells, rat ATF3 possesses an intrinsic oncogenic Jun, suggesting a role in the control of cell prolifera- potential. Moreover, the results suggest that ATF3 might tion. ATF3 mRNA rapidly and transiently accumulates induce growth factor independence by down-regulating a in response to serum (Mohn et al., 1991), Epidermal subset of the genes repressed by v-Jun. Oncogene (2001) Growth Factor and Fibroblast Growth Factor (Weir et 20, 1135 ± 1141. al., 1994), by various genotoxic stresses (Amundson et al., 1999; Chen et al., 1996; Hai et al., 1999), and after Keywords: ATF3; Jun; AP1; chicken embryo ®bro- partial hepatectomy in the regenerating liver (Chen et blasts; cell transformation al., 1996; Hsu et al., 1992). Like Jun, ATF3 might also be functionally involved in oncogenic transformation, as: (i) transformation by adenoviral protein 12S-E1A is Introduction accompanied by transcriptional activation of both c-jun and atf3 (Hagmeyer et al., 1996); and (ii) ATF3 Activating Transcription Factor 3 (ATF3; also known expression appears to be required for the maintenance as Liver Regeneration Factor 1 or LRF1; Hsu et al., of a high-metastatic state in some cancer cell lines 1991) is a member of the ATF/CREB subfamily of (Ishiguro et al., 1996, 2000). bZip transcription factors (Hai et al., 1989). ATF3 In the present study we examined whether ATF3 speci®cally binds to the 8 bp ATF/CREB consensus possesses intrinsic oncogenic potential by itself. We, motif 5'-TGACGTCA and related sequences (Hai and therefore, stably overexpressed rat ATF3 in primary Curran, 1991) and therefore contributes to the dimeric cultures of chick embryo ®broblasts (CEFs) using the transcription factor AP1 complexes. The total AP1 retroviral, self-replicating vector Rcas. In this avian binding activity in the cell is determined by the relative model of oncogenesis, single, virally-expressed, AP1 components from avian and mammalian origin can eciently transform primary cells without the need for (an)other cooperating oncoprotein(s) (Bos et al., 1990; *Correspondence: M Castellazzi Received 27 September 2000; revised 7 December 2000; accepted 19 Castellazzi et al., 1990; Vogt, 1994; Maki et al., 1987), December 2000 in contrast to mammalian cells (Hahn et al., 1999; ATF3-induced cell transformation S Perez et al 1136 SchuÈ tte et al., 1989). CEF cultures constitutively dependent promoters 56jun2-tata-luciferase, 56coll- overexpressing either ATF3 or v-Jun were compared TRE-tata-luciferase, or the corresponding tata-lucifer- with respect to their oncogenically transformed features ase control. 56jun2-tata contains ®ve copies of the in vitro and in vivo and, in addition, for the expression high-anity c-Jun:ATF2 binding site from the human levels of v-Jun target genes. c-jun promoter which eciently binds ATF3 (Hag- meyer et al., 1996). 56collTRE-tata contains ®ve copies of the proximal, high anity Fos : Jun binding Results and Discussion site from the human collagenase promoter (Materials and methods; van Dam et al., 1998). As shown in To investigate the putative oncogenic potential of Figure 2a, the activity of the 56jun2-tata and ATF3, cultures of chick embryo ®broblasts were 56collTRE-tata promoters was reduced in R-ATF3- chronically infected with either R-ATF3, a retroviral infected CEFs, respectively by 80 and 20%, when expression vector encoding rat ATF3, or, with the compared to the control R-infected CEFs. This positive and negative control vectors R-v-Jun or R. In repression by ATF3 on `jun2' ATF sites rather than the R-ATF3 infected CEFs, two major ATF3 proteins on `collTRE' Fos:Jun sites was con®rmed when were detected with an apparent molecular weight of 27 increasing amounts of ATF3 were transfected in non- and 28 kDa, which is in agreement with the size of the infected CEFs (Figure 2b). In some independently ATF3 proteins detected in mammalian cells (Hagmeyer generated primary cultures ATF3 slightly induced the et al., 1993; Hai et al., 1989) (Figure 1). In addition, a 56collTRE Fos:Jun containing model promoter, faster migrating band of about 17 kDa was observed. explaining the high standard deviation depicted in The intensity of this minor band varied from one cell Figure 2b. This induction is likely to be due to extract to another and is likely to correspond to a ATF3:Jun heterodimers, as they have been reported degradation product in CEFs. As described previously, to be able to bind to and transactivate transcription via the endogenous c-Jun levels are down-regulated in v- a consensus TRE (Hai and Curran, 1991; Hsu et al., Jun expressing CEFs (Castellazzi et al., 1990; Gao et 1991). We conclude from these data that in CEFs, like al., 1996; Kilbey et al., 1996). in mammalian cells, excess of ATF3 can repress ATF3 has been found to function as a transcrip- transcription via ATF sites. tional repressor on various promoters containing ATF We next examined the eect of ectopic expression of binding sites (Chen et al., 1994; Wolfgang et al., 1997, ATF3 on CEF proliferation and morphology. As 2000). To verify that the rat ATF3 protein was reported previously for R and R-v-Jun (Bos et al., functional in CEFs, transient transfection experiments 1990; Jurdic et al., 1995), infection with R-ATF3 did not were performed using the minimal ATF- or AP1- aect cell viability. When grown in normal medium (6% serum), all cultures became senescent after 1 ± 1.5 months in culture. However R-ATF3 and R-v-Jun-infected CEFs exhibited a more fusiform shape when compared to R-infected and to non-infected CEFs (not shown). When plated at low density (16103 cells per 100 mm plate), non-infected, R-, and R-ATF3-infected CEFs developed small foci at a frequency of 14.5, 10 and 9.5%, respectively, whereas R-v-Jun-infected CEFs gave rise to large, dense foci at an average frequency of 39.5% (Figure 4; left). When plated at a higher density (1.56105 cells per 100 mm plate), the plating eciency was the same for all cultures (80 ± 100%). Under these condi- tions, cell proliferation was measured over the following 10 days (Figure 3). The rat ATF3 expressing CEFs were found to proliferate faster than the non-transformed cultures but slower than the highly transformed, v-Jun- Figure 1 Detection of the virally-expressed v-Jun and ATF3 expressing cells. This became apparent both from the proteins in CEF cells by immunoblotting. The arrows point to the virally-expressed v-Jun, the endogenous c-Jun, and the three culture doubling times (26, 19 and 16 h for R, R-ATF3, forms of the rat ATF3. Preparation of cell extracts for Western and R-v-Jun-infected CEFs, respectively) and from the blotting was performed as described (Castellazzi et al., 1990). saturation densities (36106,56106, and 106106 con- Brie¯y, 10 ± 30 mg protein from cell extract was resolved by SDS/ tact-inhibited cells per plate). These data indicate that 10%-polyacrylamide gel electrophoresis and blotted onto nitro- ectopic expression of ATF3 in CEF induces both a cellulose membranes.
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