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The Cellular Transcription Factor CREB Corresponds To MOLECULAR AND CELLULAR BIOLOGY, Dec. 1990, p. 6192-6203 Vol. 10, No. 12 0270-7306/90/126192-12$02.00/0 Copyright C 1990, American Society for Microbiology The Cellular Transcription Factor CREB Corresponds to Activating Transcription Factor 47 (ATF-47) and Forms Complexes with a Group of Polypeptides Related to ATF-43 HELEN C. HURST,' NORMA MASSON,2 NICOLAS C. JONES,3 AND KEVIN A. W. LEE2* Gene Transcription Group, Imperial Cancer Research Fund, Hammersmith Hospital, Ducane Road, London W12 OHS,' Gene Regulation Group, Imperial Cancer Research Fund, London WC2A 3PX,3 and Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3DL,2 England Received 7 May 1990/Accepted 30 August 1990 Promoter elements containing the sequence motif CGTCA are important for a variety of inducible responses at the transcriptional level. Multiple cellular factors specifically bind to these elements and are encoded by a multigene family. Among these factors, polypeptides termed activating transcription factor 43 (ATF-43) and ATF-47 have been purified from HeLa cells and a factor referred to as cyclic AMP response element-binding protein (CREB) has been isolated from PC12 cells and rat brain. We demonstrated that CREB and ATF-47 are identical and that CREB and ATF-43 form protein-protein complexes. We also found that the cis requirements for stable DNA binding by ATF-43 and CREB are different. Using antibodies to ATF-43 we have identified a group of polypeptides (ATF-43*) in the size range from 40 to 43 kDa. ATF-43* polypeptides are related by their reactivity with anti-ATF-43, DNA-binding specificity, complex formation with CREB, heat stability, and phosphorylation by protein kinase A. Certain cell types vary in their ATF-43 complement, suggesting that CREB activity is modulated in a cell-type-specific manner through interaction with ATF-43*. ATF-43* polypeptides do not appear simply to correspond to the gene products of the ATF multigene family, suggesting that the size of the ATF family at the protein level is even larger than predicted from cDNA-cloning studies. Transcriptional activation of eucaryotic genes occurs, in and by other promoter elements (25, 49, 55). Second, mul- part, through the interaction of sequence-specific DNA- tiple cellular activator proteins interact with ATF-binding binding proteins with promoter and enhancer elements (8, sites, as described below. 24, 47, 58, 66, 77, 86). One poorly understood aspect of Gel mobility shift assays demonstrate that multiple factors transcriptional activation concerns the ability of some pro- bind directly to ATF sites (3, 15, 37, 40, 41, 43, 44, 57, 60, 62, moter elements to participate in disparate transcriptional 79, 88) and sequence-specific DNA affinity chromatography responses. Transcription factor families, the members of has enabled purification of some of these binding activities which have similar or identical DNA-binding specificities (1, 4, 15, 18, 34, 40, 44, 70, 75, 92). Of significance to the (20, 27, 35, 85, 91, 97), clearly play a major role in expanding studies described here is that a family of immunologically the activation potential of single promoter elements. How- related polypeptides of -43 and 47 kDa (referred to as ever, the mechanisms by which a variety of transcriptional ATF-43 and ATF-47, respectively [34, 40]) have been puri- responses are generated from groups of factors with appar- fied from HeLa cells and a factor of similar size, designated ently indiscriminate DNA-binding activity are not yet clear. CREB response has been Promoter elements containing the critical core motif (cAMP element-binding protein), from PC12 cells and rat brain The CGTCA (referred to here as activating transcription factor purified (70) (100). between CREB and ATF has not been estab- [ATF]-binding sites) are important for the activity of several relationship promoters that respond to different signals. ATF-binding lished, although in light of the above observations, CREB sites are implicated in positive control by the adenovirus Ela has been assumed to correspond to a member of the ATF protein (7, 9, 31, 40, 56, 57, 88, 102) and intracellular cyclic family. AMP (cAMP) (2, 14, 17, 19, 26, 38, 59, 71, 80, 82, 84, 87, 94) cDNA-cloning studies have demonstrated that an even and may also be involved in the function of enhancer more complex array of factors can bind to ATF-binding elements that respond to the human T-cell lymphotropic sites. First, it has been demonstrated that members of the virus type I (HTLV-1) transactivator p40tax (10, 28, 30, 45, Jun family can bind to ATF-binding sites when associated 69, 72) and the bovine leukemia virus transactivator p38tax with members of the ATF family as heterodimers (6, 42, 64). (51). In addition, the hydroxymethylglutaryl (HMG)-coen- Second, cDNAs corresponding to a multigene family (the zyme A reductase and 1-DNA polymerase promoters con- ATF family) encode several distinct proteins that bind to tain ATF-binding sites and are under negative control by ATF-binding sites (33, 35, 39, 50, 65). All of these proteins sterols (74) and p4Otax (46, 99), respectively. The functional bind to DNA as dimers through the action of a "leucine diversity of ATF-binding sites probably results from inter- zipper" that is required for dimerization and an adjacent action of multiple cis and trans determinants. First, the basic region that makes direct contacts with DNA (35). The ability of ATF sites to activate transcription is influenced by ATF family is therefore part of a broader class of activator sequences in close proximity to the CGTCA motif (19, 55) proteins that has been referred to as bZIP proteins (96) and includes the Jun family (11-13, 29, 36, 52, 83, 95). As is the case for other bZIP proteins, some members of the ATF * Corresponding author. family selectively form heterodimers (35), thus further in- 6192 VOL. 10, 1990 CREB CORRESPONDS TO AND FORMS COMPLEXES WITH ATFs 6193 creasing the repertoire of factors that might participate in embryonal carcinoma cells were maintained on standard specific transcriptional responses. tissue culture dishes coated with 0.1% gelatin (-300 bloom) In light of these observations it is of importance to identify from porcine skin (Sigma G-2500). For comparative experi- ATF (CREB)-related heterodimers that exist in vivo. Here, ments, cells were harvested at similar confluence one day we demonstrate that CREB is identical to ATF-47 and forms after addition of fresh media. For in vivo labeling with 32pi, complexes with ATF-43. We have identified a new group of HeLa cells in suspension were placed in phosphate-free E4 polypeptides (ATF-43 ) that share a range of properties with medium containing 5% dialyzed FBS (dialyzed against 50 ATF-43, including complex formation with CREB. ATF-43 mM NaCI) and 200 ,Ci of 32p; per ml and labeled for 12 h. polypeptides differ in their cell type distribution, suggesting Nuclear extracts were prepared by using a small-scale pro- that CREB activity may be modulated through interaction cedure as previously described (54). For in vivo labeling with with other members of the ATF family in a cell-type-specific [35S]methionine, monolayer cells were placed in methionine- manner. We also provide evidence that the cis requirements free E4 medium containing 5% dialyzed FBS (dialyzed for stable DNA binding of ATF-43 and CREB are different, against 50 mM NaCl) and 200 ,uCi/ml of [35S]methionine suggesting a mechanism that can contribute to the differen- (specific activity, 1,000 Ci/mmol, in vivo cell-labeling grade tial transcriptional activity of ATF-binding sites. from Amersham) and labeled for 12 h. Nuclear extracts from 35S-labeled cells were produced as described below. MATERIALS AND METHODS Small-scale nuclear extracts. Nuclear extracts were pre- pared by the same procedure for all monolayer cells used. Purification of ATF-43 from HeLa cells. ATF-43 was puri- Cells were washed twice with phosphate-buffered saline fied from suspension cultures of HeLa cells as previously (PBS), harvested, and resuspended in -300 ,ul of ice-cold described (40). In later preparations, the DNA-Sepharose lysis buffer (20 mM HEPES [pH 8.0], 20 mM NaCl, 0.5% column was omitted and instead the crude extract was Nonidet P-40, 1 mM DTT, protease inhibitors [0.5 mM heated for 10 min at 65°C and denatured proteins were PMSF, 2 p.g of leupeptin per ml, and 2 ,g of trasylol per ml]) removed by centrifugation (34). The supernatant was applied per 107 cells. Cells were left on ice for 5 min and centrifuged to a Biorex-70 column as previously described and step for 1 min at top speed in an Eppendorf microcentrifuge at eluted with 0.15, 0.3, 0.6, and 2 M KCl in dialysis buffer (20 room temperature. The crude nuclear pellet was resus- mM HEPES [N-2-hydroxyethylpiperazine-N'-2-ethane- pended in 60 pI of buffer (20 mM HEPES [pH 7.9], 25% sulfonic acid]-KOH [pH 8.0], 20o glycerol, 1 mM MgCI2, [vol/vol] glycerol; 420 mM NaCl, 1.5 mM MgCl2, 0.2 mM 0.5 mM EDTA, 0.1% LDAO; 0.5 mM phenylmethylsulfonyl EDTA, 1 mM DTT, protease inhibitors [0.5 mM PMSF, 2 ,ug fluoride [PMSF]; 1 mM dithiothreitol [DTT]). The 0.6 M of leupeptin per ml, and 2 ,g of trasylol per ml]) per 107 cells, fraction was dialyzed to 0.3 M and applied to a DNA affinity left on ice for 15 min, resuspended again, and left for a column prepared by using the ATF site from position -50 in further 15 min. Nuclear debris was removed by centrifuga- the adenovirus E4 promoter (40, 56).
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