Redundancy and Specificity F Mechta-Grigoriou Et Al 2379
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Oncogene (2001) 20, 2378 ± 2389 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc The mammalian Jun proteins: redundancy and speci®city Fatima Mechta-Grigoriou1, Damien Gerald1 and Moshe Yaniv*,1 1Unite des virus oncogenes, CNRS URA 1644, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France The AP-1 transcription factor is composed of a mixture transcription factors. These proteins are characterized of homo- and hetero-dimers formed between Jun and Fos by a highly charged, basic DNA binding domain, proteins. The dierent Jun and Fos family members vary immediately adjacent to an amphipathic dimerization signi®cantly in their relative abundance and their domain, referred as the `Leucine zipper' (Kouzarides interactions with additional proteins generating a and Zi, 1988; Landschulz et al., 1988). Dimerization complex network of transcriptional regulators. Thus, is required for speci®c and high anity binding to the the functional activity of AP-1 in any given cell depends palindromic DNA sequence, TGAC/GTCA (Rauscher on the relative amount of speci®c Jun/Fos proteins which et al., 1988; Gentz et al., 1989; Hirai and Yaniv, 1989; are expressed, as well as other potential interacting Ransone et al., 1989; Schuermann et al., 1989; Turner proteins. This diversity of AP-1 components has and Tjian, 1989). The dierent AP-1 dimers exhibit complicated our understanding of AP-1 function and similar DNA binding speci®cities but dier in their resulted in a paucity of information about the precise transactivation eciencies (Chiu et al., 1989; Hirai et role of individual AP-1 members in distinct cellular al., 1990; Kerppola and Curran, 1991b; Suzuki et al., processes. We shall discuss recent studies which suggest 1991). The N-terminal transactivation domain is more that dierent Jun and Fos family members may have divergent and may account for the distinct transactiva- both opposite and overlapping functions in cellular tion properties of the Jun proteins. c-Jun contains a proliferation and cell fate. Oncogene (2001) 20, docking site for the Jun N-terminal kinases (JNKs) 2378 ± 2389. which phosphorylate Serines 63 and 73 thereby enhancing its transcriptional potential and stability Keywords: cell cycle; transcription; ras signaling; (Smeal et al., 1991). The JunB protein contains a JNK apoptosis docking site but lacks N-terminal acceptor serine residues (Chiu et al., 1989) still a recent study claims that JunB can be phosphorylated by these kinases (Li Introduction et al., 1999). JunD lacks a functional JNK docking site (Kallunki et al., 1996) and is not phosphorylated by The AP-1 transcription factor participates in the these kinases. Nevertheless, JunD contains an acceptor control of cellular responses to stimuli that regulate Serine and can be phosphorylated by JNK in c-Jun/ proliferation, dierentiation, immune response, cell JunD heterodimers (Kallunki et al., 1996). death and the response to genotoxic agents or stress Comparison of c-Jun sequences among species (Angel and Karin, 1991). AP-1 is composed of Jun reveals high degree of homology. The sequence of the family members (c-Jun, JunB, and JunD) that can form mouse c-Jun protein shares 96, 81 and 72% identity either homo- or hetero-dimers among themselves. Jun with its human, chick and Xenopus counterparts, proteins also dimerize with Fos family members (c-Fos, respectively (Figure 1). The C-terminal part of the c- FosB, Fra1 and Fra2) (Angel et al., 1987, 1988a; Jun protein containing the basic region and the Curran and Franza, 1988; Halazonetis et al., 1988; Leucine-zipper is totally conserved amongst these Sassone-Corsi et al., 1988; Hirai and Yaniv, 1989). Jun species while divergences are observed in the N-terminal and Fos proteins also dimerize eciently with other transactivation domain. When compared with the transcription factors such as members of the ATF/ Drosophila Melanogaster Jun protein, sequence identity CREB (Hai and Curran, 1991) or Maf/Nrl (Kataoka et falls to 25% but remains highly similar (60%) in the al., 1994; Kerppola and Curran, 1994) families of bZip region. This observation prompted us to search proteins. for an homologous sequence in Caenorhabditis Elegans. The diferent members within the Jun or Fos We found a bZip-containing Blast sequence which has families of proteins share a high degree of sequence 34% identity and 54% similarity with the mouse bZip homology. Experiments based on the use of deletion domain. Moreover, as previously shown, the bZip and chimeric constructs of Jun and Fos proteins have domain found in the Pap1 protein, an AP-1 member revealed the modular nature of their structure. Both of the ®ssion yeast S. Pombe, has 27% identity and families belong to the bZIP group of DNA binding 46% similarity with its murine counterpart (Figure 1). The relative binding anities of distinct dimer combinations depend on the speci®c DNA sequence *Correspondence: M Yaniv and on the promoter context (Halazonetis et al., 1988; The mammalian Jun proteins: redundancy and specificity F Mechta-Grigoriou et al 2379 Figure 1 Sequence alignment of c-Jun proteins among dierent species. Mouse c-Jun protein is aligned with its human, chicken Xenopus and Drosophila counterparts. We have also added the sequence of Pap1, referred as the AP-1 member in the ®ssion yeast S. Pombe as well as the sequence of abZip-containing Blast sequence found in C. Elegans (accession number in GenBank: CAA90948.1). Each amino acid is de®ned by its one letter-code. A colour code is also used to better illustrate the similarities between c-Jun proteins. It is described as follows: short side chains amino acids (A, G) in dark blue, hydrophobic residues (V, L, P, I, M) and aromatic amino acid (F, W, Y) in green, charged amino acids (including basic residues ± R, K, H ± and acidic residues ± D, E ± in red) and nucleophilic (S, T), amide (N, Q) and cystein residues in purple. Phosphorylated Serines 63 and 73 are pointed by stars and DNA binding domain (DNA BD), nuclear localization signal (NLS) and dimerization domain are also indicated Kerppola and Curran, 1991a; Ryseck and Bravo, and S phases of the cell cycle (Lau and Nathans, 1987; 1991). Such binding sites were identi®ed in viral Almendral et al., 1988). In the following sections, we enhancers and promoters, including the polyomavirus will review the function of the three members of the (Piette et al., 1987) and papillomavirus (Thierry et al., Jun family in dierent biological processes. 1992; Bouallaga et al., 2000). Many other AP-1 binding sites have been characterized in promoters or enhancers of cellular genes encoding enzymes involved in tissue I-mitotic response remodelling, like collagenase and stromelysin, in cell cycle controlling genes such as cyclin D1 or c-jun itself, From G0 to G1 in cytokine encoding genes like IL2 (for reviews see Vogt and Bos, 1990; Angel and Karin, 1991). Proto-oncogenes frequently participate in the regula- The role of AP1 in the control of cell proliferation tion of cell proliferation through signal transduction was extensively investigated, mostly at the cellular pathways which convert extra-cellular stimuli into gene level. Several lines of evidence suggest that the Jun and expression programs. Many of these genes are also Fos proteins are important targets for mitogenic signal activated during the G0 to G1 transition when transduction pathways. First, the AP-1 binding quiescent cells are stimulated by mitogens to re-enter sequence was originally identi®ed as a TPA responsive the cell cycle. To follow carefully the dierent element (TRE) and was shown to respond to the components of AP-1 during cell growth, our laboratory tumour promoter, TPA. Treatment of cultured cells has produced polyclonal and monoclonal antibodies with mitogenic agents resulted in a strong increase in speci®c for each member of the Jun and Fos families of AP-1 binding to a TRE sequence (Piette et al., 1988; proteins. These antibodies provided valuable tools to Angel and Karin, 1991). Upon serum stimulation, determine the relative concentration and the potential many quiescent cells displayed an increase in c-jun, dimer combinations under speci®c cellular growth junB and fos mRNAs (Herschman, 1991). Based on conditions. We have ®rst analysed the variations of their rapid, high and transient transcriptional up- the Jun and Fos protein levels and AP-1 activity in regulation in response to mitogenic agents, these agents normally cycling, resting and stimulated cells (Lalle- were de®ned as `immediate early genes' or `competence mand et al., 1997). This study allowed us to classify genes' and encode products necessary for entry into G1 these proteins into three sub-groups, according to their Oncogene The mammalian Jun proteins: redundancy and specificity F Mechta-Grigoriou et al 2380 expression patterns c-Jun, JunD and Fra-2 are polymerase a and g subunits, thymidine kinase etc. AP- expressed in cycling mouse ®broblasts and are only 1 binding sites are also found in regulatory sequences mildly induced upon serum addition to the growing of cell cycle speci®c genes. For instance, the cyclin D1 cells. When cells become quiescent upon serum gene is directly regulated by AP-1 and links it to the starvation, c-Jun level decreases and JunD level cell cycle progression. Thus, the AP-1 transcription increases. JunD is partially degraded upon serum- factor does not only mediate the transduction of extra- induced re-entry into the cycle while c-Jun is strongly cellular stimuli in the G0 to G1 transition but may also stimulated under these conditions. In contrast to the provide a speci®c function in normally cycling cells. ®rst group, the basal level of JunB, c-Fos, FosB and DfosB proteins is low in cycling mouse ®broblasts but c-Jun: positive regulator of cell cycle The involvement strongly and rapidly increases after serum stimulation.