Oncogene (2001) 20, 2453 ± 2464 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis Hans van Dam*,1 and Marc Castellazzi2 1Department of Molecular Cell Biology, Leiden University Medical Center, Sylvius Laboratories, PO Box 9503, 2300 RA Leiden, The Netherlands; 2Unite 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 Jun : Fos and Jun : ATF complexes represent two classes dimers with emphasis on their roles in oncogenic of AP-1 dimers that (1) preferentially bind to either transformation in avian model systems. Previous heptameric or octameric AP-1 binding sites, and (2) are reviews on AP-1 and cell transformation include dierently regulated by cellular signaling pathways and references: (Angel and Karin, 1991; Wisdom, 1999; oncogene products. To discriminate between the func- Vogt, 1994; Karin et al., 1997; van Dam and van der tions of Jun : Fos, Jun: ATF and Jun : Jun, mutants were Eb, 1994; Hagmeyer et al., 1995). developed that restrict the ability of Jun to dimerize either to itself, or to Fos(-like) or ATF(-like) partners. Introduction of these mutants in chicken embryo Jun : Fos and Jun : ATF transcription factors: dimeric ®broblasts shows that Jun : Fra2 and Jun : ATF2 dimers complexes with variable composition and activities play distinct, complementary roles in in vitro oncogenesis by inducing either anchorage independence or growth AP-1 sub-units: members of the bZip protein family factor independence, respectively. v-Jun : ATF2 rather than v-Jun : Fra2 triggers the development of primary The main characteristic of the AP-1 complexes in the ®brosarcomas in the chicken wing. Genes encoding cell is their heterogeneity in dimer composition. This extracellular matrix components seem to constitute an heterogeneity is caused by the fact that multiple AP-1 important subset of v-Jun : ATF2-target genes. Repres- sub-units can be expressed at the same time, including sion of the matrix component SPARC by Jun is essential c-Jun, JunB, JunD, c-Fos, FosB, Fra1, Fra2, ATF2, for the induction of ®brosarcomas. Avian primary cells ATFa and ATF3. These sub-units belong to the family transformed by either Jun : Fra2 or Jun : ATF2 thus of bZip proteins, which share the same structural provide powerful tools for the investigation of the domains for dimerization and DNA binding: a basic downstream pathways involved in oncogenesis. Further region (b) and a leucine zipper (Zip). The basic region genetic studies with Jun dimerization mutants will be harbors the actual DNA-contact surface, whereas the required to be precise and extend the speci®c roles of the leucine zipper enables the formation of homo- and Jun : Fos and Jun : ATF dimers during cancer progression heterodimeric complexes with other bZip proteins, in avian and mammalian systems. Oncogene (2001) 20, which is essential for DNA-binding. The DNA-binding 2453 ± 2464. and transcription activation domains of the AP-1 sub- units can in principle function as independent protein Keywords: Jun; Fos; ATF; Maf; E1A; chicken embryo modules. However, they can in¯uence each other's ®broblasts; oncogenesis activity as a result of intra-molecular interactions, for instance in the case of c-Jun and ATF2 (Papavassiliou et al., 1995; Li and Green, 1996). Introduction Jun, Fos and ATF proteins have dimer-specific The dimeric AP-1 transcription factor complexes DNA-binding site preferences control cell proliferation and dierentiation by regulat- ing gene expression in response to positive and negative Originally, four dierent sub-classes of bZip dimers stimuli. Various AP-1 components, including c-Jun, are were discriminated, AP-1, ATF/CREB, C/EBP and essential for embryonal development and can induce Maf, based on the types of promoter elements to which oncogenic transformation upon chronic activation in these complexes were found to bind. The AP-1 dimers avian and mammalian cells. Recent studies suggest that included Jun : Jun, Jun : Fos and Jun : Fra, which bind the c-Jun dimer partners and their target gene with high anity to the seven base pair consensus preferences are important determinants in these sequence TGA G TCA, a phorbol ester- and growth processes. Here, we will review the dierences between factor-inducible element (Figure 1). The ATF/CREB the Jun : Jun, Jun : Fos and Jun : ATF classes of AP-1 family members CREB, ATF1, ATF2 (also called CREBP-1 or mXBP), ATFa, CREBP-2, ATF3, ATF4 and ATF6 bind with high anity to the octameric *Correspondence: Hans van Dam cyclic AMP-responsive element (CRE) TGA CG TCA Jun : Fos versus Jun : ATF in oncogenesis H van Dam and M Castellazzi 2454 Figure 1 Proposed model for Jun-dependent transformation based on studies with avian and mammalian cells. Details are provided in the text and in McCarthy et al. (1995) and Wisdom (1999) (Hai et al., 1989). This element only diers by one dimers, but do not combine with the other ATF nucleotide from the heptameric AP1 binding site. proteins. The members of the second sub-class, ATF2, The original distinction between AP1 and ATF/ ATFa, CREBP-2, ATF3, ATF4 and ATF6 combine CREB is somewhat confusing, as Jun : Jun and both with themselves and with speci®c Jun and/or Fos Jun : Fos dimers can also bind to ATF/CREB sites, family members. For instance, c-Jun forms stable depending on the ¯anking sequences. Moreover, the dimers with ATF2, ATF3 and ATF4, but not with ATF/CREB family members can, in fact, be divided ATF1 and CREB. c-Fos and Fra-1 can heterodimerize into two distinct sub-classes, based on their partner with ATF4, but not with ATF2 and ATF3 (Ivashkiv et speci®city. The members of the ®rst sub-class, CREB al., 1990; Benbrook and Jones, 1990; Chatton et al., and ATF1, form homodimers or CREB : ATF1 hetero- 1994; Hai and Curran, 1991). Both ATF2 homodimers Oncogene Jun : Fos versus Jun : ATF in oncogenesis H van Dam and M Castellazzi 2455 and c-Jun : ATF2 heterodimers bind with high anity The expression of more than one AP-1 component is to degenerated ATF sites with the consensus motif under positive and negative AP-1 (auto-) control. The G T /TA CN TCA (Figure 1). However, c-Jun : ATF2 c-jun and atf3 promoters can be activated by c- and ATF2 : ATF2 show dierences in their relatively Jun : ATF2 and/or ATF2 : ATF2 via Jun : ATF binding anities for more degenerated 8 bp ATF-like motifs sites, whereas the atf3 promoter is inhibited by ATF3 (Benbrook and Jones, 1990, 1994). (Angel et al., 1988; Stein et al., 1992; van Dam et al., Jun, Fos and ATF family members can also bind to 1993, 1995; Liang et al., 1996; Wolfgang et al., 2000). DNA upon association with certain Maf (Motohashi et The c-jun promoter can be inhibited by JunB, c-Jun al., 1997; Kerpola and Curran, 1996), C/EBP (Ka- and c-Fos (Chiu et al., 1988; Park, Ponta and Herrlich, geyama et al., 1991), and non-bZip members factors, unpublished) and c-Fos is also able to inhibit its own like NF-kB (Stein et al., 1993), NFAT (Jain et al., promoter (Sassone-Corsi et al., 1988; Konig et al., 1993; Chen et al., 1998), and Smad (Liberati et al., 1989). In contrast, c-Jun : Fos and c-Jun : Fra2 posi- 1999). This can direct AP-1 components to promoter tively regulate the expression of Fra1 and Fra2 sequences that only slightly resemble consensus AP1 (Bergers et al., 1995; Sonobe et al., 1995; Schreiber et and ATF motifs. This variation in dimer partner and al., 1997; Matsuo et al., 2000). This feed-back control DNA binding site speci®city is assumed to provide AP- allows ®ne-tuned regulation of Jun : Fos and Jun : ATF 1 sub-units with a high level of ¯exibility in gene activity over longer periods of time (Figure 1). regulation potential. Jun : Fos and Jun : ATF dimers as targets of (activated) Differential control of Jun : Fos and Jun : ATF activity in oncoproteins the cell The activity of Jun : Fos and Jun : ATF complexes can A large amount of studies have shown that Jun:Fos be regulated at multiple levels. The abundance of the dimers play an important role in oncogenesis. The c-jun sub-units can be controlled via: (i) regulation of the and c-fos genes were identi®ed as retrovirally activated synthesis and stability of the respective mRNAs; and genes with oncogenic potential in avian and mamma- (ii) regulation of protein stability, e.g. via stimulus- lian cells. Wild-type c-Jun and Fos(-related) proteins dependent degradation via the ubiquitine pathway are required for oncogenic transformation induced by (Musti et al., 1997). In addition, the DNA-binding constitutively active Ras and Ras-related factors and transactivating capacities of AP-1 components are (Lloyd et al., 1991; Smeal et al., 1991; Binetruy et al., controlled through post-translational modi®cation (in- 1991; Johnson et al., 1996; Saez et al., 1995; Suzuki et cluding phosphorylation) and protein ± protein interac- al., 1994). The levels and/or activity states of c-Jun and tion (reviewed in Angel and Karin, 1991; Karin et al., c-Fos are elevated by Ras via the JNK/SAPK and 1997). ERK pathways (Davis, 1999; Karin et al., 1997; see The actual activities of Jun : Fos and Jun : ATF above). The levels of Jun : Fra1, rather than of depend on the cell type, its dierentiation state and Jun : Fos, are upregulated in Ras-transformed mouse the type of stimuli it has received.