Nuclear oncogenes

Introduction

Nudear oncogenes

Jacques Chysdael and Moshe Yaniv

lnstitut Curie, Centre Universitaire, Orsay, and lnstitut Pasteur, Paris, France

, Ample evidence has accumulated in recent years to establish that most, if not all, nuclear proto-oncogenes are in fact sequence-specific DNA-binding proteins that modulate gene expression. Their synthesis or activity is modulated by extracellular signals or by cross talk between different classes

of transcription factors.

Current Opinion in Cell Biology 1991, 3:484-492

The identilication of a number of cellular proto-oncogenes with a nuclear localization suggested that at least some, such as myc, jis, myb, or ets, might in fact be transcriptional activators. This hypothesis was proven recently for most of these proto-oncogenes either by demonstrating direct DNA-binding specificity and transcriptional activation or merely by their high degree of homology with purified transcription factors. In this review, we focus on the recent demonstration of DNA- binding and transcriptional activation or repression properties of some of the nuclear oncogenes, limiting our- selves to oncogenes primarily identified in retroviruses. We will discuss the possible cross talk between c-jun and c-b nuclear proto-oncogenes and steroid or vitamin hormone receptors. Finally, transcriptional and post-tran scriptional regulation of nuclear oncogene synthesis or activity is discussed.

ErbA

The v-e&4 oncogene is found, together with v-e&B, in the genome of the avian erythroblastosis virus. Although v-e&3 is sufficient to induce erythroleukemia in chickens, v-e&A contributes to v-e&B-induced transformation of erythroblasts by blocking their terminal differentiation into erythrocytes and by reducing their growth require- ments. The v-e&B oncogene encodes a truncated version of the chick epidermal growth factor/transforming growth factor-a receptor that displays a constitutive protein tyrosine-kinase activity. The product of v-e&A is a truncated and mutated version of the chicken c-erbAa- encoded thyroid hormone (T$ receptor [l].

The genome of vertebrates contains, in addition to c-e&a, other e&A-related genes that encode either dis-

tinct TSR (e.g. c-erbAP> or non-ligand binding forms of these receptors [2]. ErbA proteins are part of a larger family of l&and-dependent transcriptional activators, which includes the receptors of glucocorticoid and steroid hormones, vitamin D3, and retinoids. The c-e&Aa-encoded TJR share with these receptors a similar modular organization that includes a carboxy-teti- nal ligand-binding domain and a central region containing two zinc-finger motifs responsible for specific DNA- binding [ 31. The ligand-binding domain includes, in addition to the subdomains directly involved in Tj binding, a dimerization interface important for both homodimer and heterodimer formation with some other receptors [4,5*], and domains involved in the modulation of transcriptional activity [ 6*,7**].

Genes regulated by T$s contain c&acting elements (T$Es) which are variations of an AGGTCA motif present as multiple direct or inverted repeats in their promoter region and which bind TjR with high affinity, ir- respective of the presence or absence of hormone. Un- liganded receptors bound to these elements act as repressors of cislinked promoters and, upon binding of T , 93.

they are converted into transcriptional activators [8,

The oncogenic v-ErbA protein differs from c-ErbAa/T3R by a nine-amino-acid deletion and nine amino acid substitutions in the ligand-binding domain, two amino acid substitutions in both the DNA-binding region and the amino-terminal domains, and the deletion of the first 12 amino-terminal residues [ 11. Because of the extensive mutations in the ligand-binding domain, v-ErbA fails to bind hormone and is impaired in its ability to homo- or heterodimerize (H Samuels, personal communication) [lOI. Although it is still unclear whether the amino-acid substitutions in the DNA-binding domain affect binding specificity, v-ErbA shows a reduced afl?nity compared with

Abbreviations AMV-avian myeloblastosis virus; BR-basic region; CR-glucocorticoid receptor; CRE-glucocorticoid response element;

H&helix-loophelix; LR-leucine repeat; PRC-protein kinase C, R-receptor; T,--thyroid hormone; TCR-T-cell receptor; TPA-12-0-tetradecanoyl-phorbol-acetate; TRE-TPA response element.

@ Current Biology Ltd ISSN 0955-0674

Nuclear oncogenes Ghysdael and Yaniv 485

c-ErbA for model T$Es (J Ghysdael, unpublished data). In transient co-transfection assays, vErbA acts (to a vari- able extent depending on the T.$E analysed) as a dominant repressor of TSR-mediated transcriptional activation [8,9]. Consistent with these observations, v-ErbA blocks erythroblast differentiation whereas a similarly expressed c-ErbAu accelerates differentiation in the presence of Tj [7**,11,12*]. This block of differentiation by v-ErbA correlates with the constitutive suppression of three erythrocyte-specific genes (carbonic anhydrase II ; the anion transporter Band 3, and the heme biosynthe- sis enzyme, ALA-S [7**,11]. Of these, only carbonic anhydrase types II is a direct target for c-ErbAor and v-ErbA [12] (M Zenke, unpublished data). Three regions of v- ErbA have been shown to be important to its function as an oncogenic protein: the ligand-binding domain [7**], the DNA-binding domain [ 131, and two phosphorylated residues in the amino-terminal domain [14-l. The relative contributions of these different regions in the regulation of carbonic anhydrase II, ALA-S, Band 3 or of other target genes yet to be identilied, remains to be clarified. The identification of additional target genes will also help to resolve whether v-ErbA acts as an antagonist of Tj-regulated genes only or whether it also interferes with other regulatory circuits.

Ets

The c-e&Z gene is the cellular progenitor of the vets oncogene, which together with v-m@, is responsible for the oncogenic properties of E26, a retrovirus that induces a mixed myeloid/erythroid leukemia in chickens and transforms myeloblasts and erythroblasts in tissue culture.

c-e&l is the prototype of a gene family which includes c-e62, erg, elk- I, e&2, and spi- Z/Pu-1 in vertebrates and E74 in Drcsophih melunogaster. Although it has been known for some time that c-Etsl and c-Ets2 were nuclear, chromatin-associated proteins able to bind to non- specific DNA in r&-o [15], the biochemical function of members of the Ets family was only characterized recently. Etsl and D. mehnogaster E74 were shown to bind to specific DNA sequences [ 16**,17*] and Etsl, Ets2 and Pu-l/Spi-1 were shown to be sequence-specific transcriptional activators [ 18**,19*,20**]. With the exception of E74 [ 17.1, no systematic investigation of the binding specificity of Ets proteins has been reported. It is clear, however, that these proteins all bind to variations of a purine-rich sequence that includes an A/C GGAA core motif which act as c&acting responsive elements in the context of various promoters [18**,19”,2@*]. The only genuine targets identified so far in cellular genes are Etsl and Ets2 binding sites in the enhancers of the T-cell receptor (TCR) genes u and j3 (H Prosser et a~!, unpublished data) [21**] and the accumulation of E74 at early or late ecdysone-inducible puffs [ 17.1. Interestingly, co- transfected Etsl acts as a repressor of the activity of the TCR-b enhancer (H Prosser et al, unpublished data).

The domain of Etsl and Spi-l/Pu-1, required for nuclear transport and DNA-binding is localized in their carboxy terminal domain [16**,19**, 221. This domain of Etsl shares with all other members of the Ets family, a region of 85 amino acids which will most probably be sufficient for specific binding to DNA This region fails to show any homology to DNA-binding motifs of other transcriptional activators. Etsl also appears to contain an intrinsic transactivation domain [20**,23] but the precise localization of this (these) domain(s) are as yet unknown.

Available evidence indicates that members of the Ets family could regulate the expression of tissue-specific genes. Expression of both Etsl and Ets2 is detectable in a wide variety of tissues but preferential expression of both genes is observed in selective cell types both in the embryo and adult tissues. For example, expression of c-e&l and c-ets2 is regulated reciprocally during T- cell activation [24] and c-et& is as an immediate- early gene in monocytes and macrophages [25=]. In contrast, spi-Z/Pu-1 and elk genes appear to be expressed in more restricted cell-types [19*,26]. Consis- tent with a regulatory role, Etsl and Et.52 are short- lived proteins that are, furthermore, subject to rapid and transient changes in their phosphorylation status in response to the triggering of specilic transduction pathways [27-291. Recent evidence also indicates that Etsl co-operates with Jun/Fos for transcriptional activation of the Py promoter [20**] and that the target element for Etsl repression in the TCR-P enhancer is a 12-O-tetradecanoyl-phorbol-acetate (TPA)-responsive element (Prosser et al., unpublished data). Etsl and Ets2 appear, therefore, to be transcriptional factors or subunits of transcription complexes which mediate the effects of ex- traceuular signals triggering Ca2+ and protein kinase C (PKC) transduction pathways.

The v-e& oncogene of avian leukemia virus ~26 encodes the carboxyterminal domain of a tripartite Gag-Myb- Ets nuclear fusion protein of 135kD. The progenitor of v-e& is a chicken-specific splice variant of c-e& I which encodes an Etsl protein that differs at its amino terminus from the major phyiogenetically conserved 55 kD form of Ets 1 [30]. In addition, Etsl differs from v-Ets in its carboxy-terminal domain by three amino acid substitutions and the replacement of the very last 13 carboxy- terminal residues by 16 amino acids of unknown origin. The vets oncogene is not required for myeloid transformation by ~26 but both v- M$ and v- ets are instrumental in erythroblast transformation [31*,32,33*]. This require- ment can be fulfilled by v-q& and v-e&s being expressed as separate entities or as a fusion protein [33* I. The ability of ~26 to induce leukemia in chickens, however, is only observed with Myb-Ets fusion proteins, a property for which the amino-terminal 188 amino acid residues of vets are not required [ 33.1. The molecular basis for the cooperativity between Myb and Ets is unknown.

The @i-Z/Pu-1 gene also appears to be involved in erythroid transformation Abnormal expression of @l/Pu-1 as the result of proviral insertion is one of the hallmarks of spleen-focus-forming virus-induced ery-

486 Nucleus and gene expression

throleukemia [34*]. Because @I/Pu-1 is not expressed in normal erythroid cells, and because the @oi- 1/Pu-1 protein that is expressed in transformed erythroblasts is not mutated [ 351, it would appear that it is the ectopic high- level expression of @pi- I/Pu-1 that contributes to disease development. It would be interesting to know to what extent genes regulated by vets and spi-I/Pu-1 in transformed erythroblasts actually overlap.

Jun and Fos

The transcription factor, AI-l, was first deiined as a nuclear protein binding to the TPA response element (TRE > found in genes such as coUagenase or metallothionein. It was later shown to contain the products of two protooncogene families, jun andf? either as Jun homodimers or as Jun/Fos heterodimers. Dimerization is mediated by the leucine repeat (or leucine zipper) with two a-helices forming a coiled-coil structure. In the heterodimer both Jun and Fos contribute to transcriptional activation [ 361. The structural homology between c-Jun and c-Fos make it plausible that the basic region of c-Fos will directly contact the TGACTCA or TRE element. This was indeed conIirmed by direct ultraviolet crosslinking [37-391 and domain switch with cJun [40]. It is, however, not com- pletely clear whether recognition is asymmetrical. Other partners for heterodimerization with c-Jun are some of the members of the &IMP-response-element-binding factor /activation transcription factor family, although its sig- nificance in viva is unclear [41, 421. Finally, a crucial cysteine in the basic DNA-binding domain of c-Jun was shown to be sensitive to redox potential [43]. Two lines of evidence suggest that a segment in the amino terminus of cJun is a subject for negative regulation by the cell. Firstly, even though overexpression of wild-type murine or avian c-Jun transforms primary chicken embryo iibro- blasts [44*--46], the frequency is increased upon intro- ducing the 27-amino-acid deletion present in v-jun into its wild-type counterpart [44-l. Roughly the same region was shown to be involved in the modulation of c-Jun transcriptional activity in HeIa cells in tCt!o and in t&-o [ 47**,48].

The reasons for the existence of multigene families for many of the nuclear oncogenes is not fully understood. At least three members of the jun family [36] and four members of the fclri family are known [ 36,491. Differences were observed in the transforming and transactivating properties of c-Jun and JunB, excess of the latter inhibits transcription activation and transformation by the first [50*,51*]. Furthermore, JunB and c-Jun differ in their response to two major signal transduction pathways. While JunB as with c-Fos is stimulated by the activation of both the PKC and the protein kinase A-mediated pathways, c-Jun is stimulated only by the first pathway and this stimulation is blocked by elevated CAMP concentration. The inhibition of cJun expression by the cAMP-dependent pathway may be related to the growth inhibitory effect of this pathway in libroblasts [52,53].

Co-operation or negative interference behwen c-jun and C-/OS proto-oncogenes and steroid or vitamin hormone receptors Several recent publications demonstrate that a complex interconnection exists between these two classes of transcription factors. The osteocalcin gene promoter is positively regulated by vitamins A and D3 through a hormone- receptor response element. The sequence of this element also includes an API binding site, and transfection experiments revealed that vitamin-induced transcription is inhibited by excess c-Jun and c-Fos, two components of the AP-1 complex [ 54*]. A diiferent picture was obtained for the estrogen regulation of the ovalbumin gene. In this case, hormonal activation of the promoter was strongly enhanced in the presence of cJun and c-Fos, and did not seem to require direct binding of the receptor to DNA [55**]. Finally, a glucocorticoid response element (GRE) present in the promoter of the mouse proliferin gene required both glucocorticoid receptor (GR) and c-Jun for positive action while c-Jun and excess c-Fos converted it into a negative GRE [56**].

Another fascinating interaction was revealed through the study of antagonism between tumor-promoter stimulation and glucocorticoid inhibition of the transcription of the collagenase gene, an enzyme involved in inllamma- tion [57**]. This study demonstrated that the hormone- bound receptor strongly inhibits the transcriptional activation by AP-1 without affecting DNA-binding. Inhibition is reciprocal because excess AI-1 inhibits glucocorticoid- dependent mouse mammary tumor virus transcription. This report was confirmed and extended by several other groups [ 58**60**], who also tried to define the segments of Jun, Fos and the receptor, that are involved in cross inhibition. For the receptor, DNA-binding domain with unimpaired DNA-binding activity is essential, while the transactivation domain(s) are dispensable. For c-Jun, the leucine repeat is essential according to Schulle et al. [6@*] while the transcriptional domain is not. Different results, however, were obtained for c-Fos-dependent inhibition. In this case, a region preceding the dimerization DNA-binding domain is involved in repression [58**]. Similar results were obtained in one of our laboratories for the inhibition of estrogen-receptor activity in human breast cancer cells. Both the amino-terminal transactiva tion domain and the leucine repeat were essential for inhibition. The latter may be required more for the correct conformation or nuclear localization of cJun than for its direct inhibitory effect [61].

MYb

The c-m@ gene is the cellular progenitor of the v-m@ oncogene of avian leukemia viruses, avian myeloblastosis virus (AMV) and ~26, and is also the target for retroviral insertion in mouse myeloid leukemias and chicken bursal lymphomas [62]. Since its recent review [63], only limited additional information has been gained about the function of the c-m+ en-

Nuclear oncogenes Ghysdael and Yaniv 487

coded proteins (c-Myb) and their oncogenic forms. Mam- malian c-Myb as well as the product of the related B-m@ gene [64], have been shown to bind to specific DNA sequences that conform to the general consensus Py AACG/TG [65**]. These sequences serve as cis-acting elements for Mybinduced transactivation of a variety of promoter-reporter constructs, including the Myb binding sites found in the transcriptional regulatory region of mim-I, a myeloid-specific gene identified as a direct target for v-Myb in E26-transformed myeloblasts [66**].

Although an extensive structure-function analysis is not yet available, three domains have clearly been identified in c-Myb. The first domain is formed by three imperfect repeats of 51-52 amino acids (R,, RZ, Rj) of which only R2 and Rj are sufficient for specific binding to DNA [67*]. The Myb DNA-binding domain is unique in that each repeat would fold into three helical segments, two of which could form a helix- loop-helix (HLH) structure similar to that of homeodomains [68]. Recently, combinations of molecular modeling and site-directed mutagenesis have provided experimental support in favor of this model [69*,70**] (S Ishii, personal communication). The second and third domains are localized in a more carboxy-terminal position and iniluence the transcriptional activity of c-Myb, either positively or negatively 1711. Phosphoryla- tion of c-Myb on serine residues 11 and 12 by casein kinase II suppresses binding to specific DNA sequences [72.].

The strict involvement of oncogenic Myb proteins in hematopoietic cell transformation is likely to be linked to the almost exclusive expression of c-rn-vb in hematopoietic tissues. Furthermore, oncogenic Myb proteins have lost either one or both of the amino- and carboxy-terminal negative regulatory domains of c-Myb. The impli- cation is, therefore, that oncogenic Myb proteins would display an increased transcriptional activity on genes nor- mally regulated by c-Myb. Reality will undoubtedly prove to be more complex because such a model overlooks the fact, for example, that the target-cell specificity (and target genes [ 66**] > of the v- myb oncogenes of AMV and E26 are different both in the myeloid and erythroid lineages [33*] and that transactivation by Myb can also occur in the absence of DNA binding [73]. In addition, some forms of Myb have been shown to act as dominant negative repressors of c-Myb function [74]. Clarifi- cation of these issues will be helped considerably by the identification of Myb-responsive genes directly involved in transformation.

MYC

An enormous amount of experimental evidence has been accumulated that implicates the c-myc proto-oncogene and the related L-myc and N-myc genes in the control of normal cellular proliferation and of deregulated and/or mutated versions of these genes in a wide variety of onco-

genie processes [ 631. The biochemical function of Myc is, however, still unknown. Myc proteins, as well as their oncogenic or alleged oncogenic versions, are nuclear and share at their carboxy terminus an 85-amino-acid domain which includes a basic region (BR), a HLH motif and a leucine repeat (LR) [ 751. This motif has recently been shown to be shared by two transcriptional activators, USF [76*] and AP-4 [77*]. For both AP4 and USF, the BR- HLH motif is sufficient for DNA binding whereas the LR motif is required for dimerization and this contributes to efficient binding to DNA as well. The response element recognized by these factors includes a symmetri- cal core sequence, CAXXTG, also present in the binding sites of a large family of proteins which regulate differentiation of speciiic cell lineages. These homologies have recently allowed the demonstration of Myc binding to sequences containing a CACGTG core motif, presumably as a homodimer (E Ziif, personal communication) [78**]. The extent to which Myc is able to heterodimerize with other protein-containing HLH or LR motifs remains to be established. This question is important because the type of dimer formed would be expected to affect DNA-binding specificity and hence target-gene selectivity. Deletion or mutation of the HLH-LR region of c-Myc is deleteri- ous to Myc-induced transformation of fibroblasts [79-81] or selectively affects transformation of specific cell types [81], The implications of these findings is that normal and oncogenic Myc proteins could act as transcriptional regulators.

Although several reports have shown Myc to regulate the activity of a variety of promoters/enhancers in truns, or induce or repress the expression of specific genes [ 83,84*], no evidence has been provided to conlirm that these effects were the consequence of Myc binding to regulatory sequences within these genes. Direct targets for Myc gene transcriptional activation remains to be identified but will probably include genes expressed in Gl, required for entry of progression into the S phase.

Rel

The c- rel gene is the cellular progenitor of the v- relonco- gene of avian reticuloendotheliosis virus (REV-T), a virus which causes lymphomas in young chickens. The 80kD c-ref-encoded protein (c-Rel) has recently been shown to belong to the NF-xB/KBF-1 family of transcriptional activators [85**,86**]. These transcriptional factors bind to similar sequences [GGG PU (CAT) T Py Py (CAT) C] that act as cz%acting elements for speciIic transcriptional activation of a variety of immediate-early genes and of class I major histocompatibility complex (MHC) genes, respectively.

NFxB is a heterotetramer consisting of two subunits of 50 kD and two subunits of 65 kD, which is maintained in a latent form in the cytoplasm by its association with an inhibitory subunit, IxB. Activation of cells by a variety of agents induces the phosphorylation of IxB and its subsequent dissociation from NF-xB, which then translocates


to the nucleus to activate gene transcription. The region of homology between NF-xB/KBF-1 and rel proteins is restricted to 323 amino acids involved in both DNA binding and dimerization [85**,86**]. The DNA-binding motif of Rel proteins is novel because this domain does not share any homology with known DNA-binding motifs. Consistent with these structural homologies, both the v-Rel and c-Rel proteins have been shown to bind to xB sites [85”,87**] and both are found associated with similar proteins in the cytoplasm of resting lymphoid cells [88,89]. Activation of T cells with phorbol esters results in the translocation of c-Rel into the nucleus, al- beit with slower kinetics than those of NF-xB [ 87**,90]. Furthermore, c-Rel appears to contain a strong transcriptional activation domain at its carboxyl terminus [91]. Deletion of this domain as it occurs in the oncogenic v-Rel protein is likely to contribute to the inability of v-Rel to activate transcription when bound to xB c&-acting elements in reporter plasmids [87**]. In fact, v-Rel appears to act as an antagonist of NFxB-mediated transcriptional activation in T cells [87**]. This property is probably relevant to the oncogenic properties of v-Rel since an overexpressed fuU-length c-Rel fails to transform lymphoid cells, whereas a truncated carboxy-terminal version of c-Rel is oncogenic [91]. At the molecular level, v-Rel could act either as a competitor for binding of cellular members of the rel gene family to relevant enhancer sequences, or as a competitor for proper heterodimer formation between members of the Rel family or with other cellular proteins, therefore disrupting the normal signalling pathways that occur through the regulation of these associations. v-Rel is essentialty cytoplas- mic in transformed lymphoid cells [92]. It can also, however, induce transformation when artificially concentrated in the nucleus [ 921, suggesting that both types of mecha- nisms could contribute to the full oncogenic potential of v-Rel. The identilication of v-Rel target genes relevant to ceU transformation will be required to determine these issues.

Conclusions

This review clearly demonstrates that the transcriptional modulators belonging to different classes as judged by their structure, can be rendered oncogenic when incor- porated into retroviruses. The viral oncogenes differ from their cellular homologues by mutations that either render them insensitive to signal-transduction-dependent modu- lations or that impair or modify their normal function. Constitutive activity of mutant oncogenes that are involved in the control of growth-regulated genes or even overexpression of their wild-type counterparts in some cases will confer a transformed phenotype to cells. In other cases, mutant factors will interfere with the function of their normal counterparts and induce transformation by blocking differentiation. Finally, the list of transcriptional modulators that were identified as oncogenes is certainly not exhaustive. We did not deal in this review

with several cases recently described where the genes for transcription factors are modified by genomic transloca- tions in certain malignancies. Furthermore, we did not discuss the function of the p53 and Rb (retinoblastoma) tumor suppressor genes that may also be transcriptional modulators.

References and recommended reading

Papers of special interest, published within the annual period of review, have bezn highlighted as: . . .

1.

2.

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-1.

5. .

of interest of outstanding interest

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Identication (through screening of a macrophage cDNA library with an oligonucleotide to the Pu-box element in the promoter of a MHC Class Il gene) of a factor that binds to a purine-rich sequence centered on

the Pu-box (GAGGAA). Pu-I which is expressed in B-lymphocytes and macrophages shares 41% amino-acid homology in its carboxy-terminal DNA-binding domain with that of Etsl and Ets2.

20. W.ww~ B, Wmy~ C, FLORES P, BEGUE 4 &PRINCE D, . . STEHEUN D: The c-e& Protooncogenes Encode Transcription

Factors that Cooperate with c-Fos and c-Jun for Transcrip tional Activation. Nature 1990, 346:191-193.

Co.transfection experiments which demonstrate that Etsl and Ets2 ac. tivate transcription of the enhancer of the PoIyoma virus through a purine-rich sequence centered around the core sequence AGGAA and which partially overlaps with an adjacent AF-1 site. Etsl is found to cooperate with Fos and Jun for activation of transcription of the Py enhancer.

21. Ho I, BHAT N, Gorrsclcw I+ UNIXTEN T, THOMSON CB, Phpfi . . TS. IIIDEN JM: Sequence-specific Binding of Human Etsl

to the T cell Receptor and Gene Enhancer. Science 1990, 250:814-818.

The screening of a T-cell cDNA library with an ollgonucleotide corre- sponding to one of the known protein binding sites in the TCR-a-gene enhancer, and the identification of Etsl as a protein specUicalIy binding to a purine-rich sequence that includes a central AGGAT core. Disrup- tion of this binding site reduces enhancer activity in T.ceUs.

22. BOLILLIKOS KE. POCNONEC P, RABAULT B, BEGUE 4 GHYSDAEL J: Definition of an Etsl Protein Domain Required for Nuclear Localization in Cells and DNA-binding Activity In Vitra Md Cell Biol 1989, 9:571&5721.

23. SENECA S, Puw.mhwm B, BNUY M, GHV~DAEL J, CRABEEL M: Etsl. when Fused fo the Gal 4 DNA-binding Domain, Efficiently Enhances Galactose Romotor Dependent Gene Expression in Yeast. Oncogene 1991, 6:357-360.

24. BHAT N, THOMP~~N CB. LINIXTEN T, JUNE C, FUJIWARA S, KOIZLIMI S. FISCHER RJ. PAPAS TS: Reciprocal Expression of Human Etsl and Ets,! Genes During T-cell Activation: Reg ulatory Role for the Rotooncogene Etsl. Proc Nut1 Acad Sci UW 87~37233727.

25. BOULLIKOS K, P~CNONEC P. SARIBAN E, BNUY M, ~AGROU C, . GHY~DAEL J: Rapid and Transient Expression of Ets2 in Ma-

fure Macrophage Following Stimulation with cMGF. LPS and PKC Activators. Genes Deal 1990, 4:401309.

Reports the rapid and transient induction of c-e&2, typical of immediate- earb response genes, following treatment of non-dividing monocytes and macrophages with agents responsible for the acquisition of macrophage functional competence.

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RAO VN. HUEBNER K, IS~BE M, RUSHDI A, CR~CE C, REDDY SP: elk, Tissue Specific e&related Genes on Chromosome X and 14 Near Translocation Breakpoints. Science 1989, 24416670.

POCNONEC P. BOUUKOS KE, GF.SQU~ERE JC, STEHELIN D, GHI’SDAEL J: Mitogenic Stimulation of Thymocytes Result in the Calcium-dependent Phosphorylation of c-e&I Roteins. EMBO J 1988, 7~977-983.

FUJIWARA S, FISHER RJ, BHAT N. MORENO Dw DE LA ESPINA S, PAPAS TS: A Short-lived Nuclear Phosphoprotein Encoded by the Human ets2 Roto-oncogene is Stabilized by Activation of Protein Kinase C. IMOI Cell Biol 1988, 8:47004706.

POGNONEC P, BOUL~KOS KE, BOSSELUT R, BOYER C, SCHMITT- VERHUIST AM, GHY~DAEL J: Identification of an Etsl Variant Protein Untiected in its Chromatin and In Vitro DNA- binding Capacities by T-cell Antigen Receptor Triggering and IntraceUuIar Calcium Rises. Oncogene 1990, 5603-610.

IIPRINCE D. DUIERQUE M, RUO-PLNG L, HENRY C, FLOURENS A, DEBUIR!Z B, STEHEUN D: Alternative Splicing Within the Chicken c-e& I Locus: Implications for Transduction within the E26 Retrovirus of c-e& Protooncogene. J Viral 1988, 62:32333241.

GOIAY J, mol\ol M, GRAF T: A Single Poiit Mutation in the v-e& Oncogene Affects Both Erythroid and Myelomonocytic CeU Ditlerentiacion. Cell 1988, 55:1147-1148.


Describes the isolation of a mutant of E26 that was found to contain a single-point mutation in the DNA-binding domain of v-efs This mutant is temperature-sensit& for erythroid transformation and caused an al- teration toward a more mature phenotype of transformed myeloid cells as compared to wild-type E26.

32. NLJNN hlF, HUN~IR T: The ets Sequence is Required for In- duction of Erythroblastosis in Chickens by Avian Retrovirus E26. J Viral 1989, 63:398-402.

33. M!ZIZ T, GRAF T: V-my6 and v-ets Transform Chicken Ery- . throid Cells and Cooperate Both in Trans and Cis to In-

duce Distinct Differentiation Phenotypes. Genes Det 1991, 5:36+380.

Reports a comparison of the transforming properties in the myeloid and etythroid lineages of viruses expressing v-Myb, v-Ets, v.Myh and v-Ets or the natural E26 Myb.ets fusion proteins. v-Myb was found to be sufficient to induce transformation of myeloid cells whereas both v-Myb and v-Ets increased the self-renewal capacity of etythroblasts. The transforming efficiency of both oncogenes is enhanced if they are co. expressed as separate proteins or as a fusion product.

34. MORF.AU-GACHEUN F, TAV~AN A, TA~~BOUFUN P: Spi-1 is a Puta- . tive Oncogene in Virally-induced Murine Erythroleukemias.

Nature 1988, 331:277-280. Reports the integration of a SFFV provirus at a common locus (pi 1) in over 95 % of the cases of SFFV.induced leukemias. This is accompanied by the actimtion of the expression of a 4 kb pi- 1 RNA in these tumors.

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PAUL R, SCHUElZE S, KOW Sl Ko7~ CA, EAT D: The St@1 Proviral Integration Site of Friend Erythroleukemia Encodes the e&related Transcription Factor Pu-1. J I’irol 1991, 65464467.

VOGT PK. BOS TJ: jun :Oncogene and Transcription Factor. Adv Cancer Res 1990, 55:1-55.

RISSE G. Jooss K. NELIBERG M, BRLJLLER H.J, MUUIR R: Asymmetrical Recognition of the Palindromic AP-I binding Site (TRE) by Fos Protein Complexes. WIBO J 1989, 8:382>3832.

HIRAI Sl, YAN~V M: Jun DNA-binding is Modulated by Muta- tions Between the Leucines or by Lnteraction of Fos with the TGACTCA Sequence. Neul Biol 1989, 1:181-191.

H~RAI Sl, BOLJRACHOT B. YANIX~ M: Both Jun and Fos Con- tribute to Transcription Activation by the Heterodimer. Onwgene 1990, 5~39-46.

NAKABEPPU Y, NATHANS D: The Basic Region of Fos Mediates Specific DNA Binding. EMBO J 1989, 8:3833-3842.

BENEIR~OK DM, JONES NC: Heterodimer Formation Between CREB and JUN Proteins. Oncogene 1990, 5:29%302.

MACGREGOR PF. ABATX C, CURRAN T: Direct Cloning of Leucine Zipper Proteins: Jun Binds Cooperatively to the CRE with CRE-BPl. Oncogene 1990, 5:451458.

&ATE C, PATEL 1 RAUSCHER FJ, CLIRRAN T: Redox Regulation of Fos and Jun DNA-binding Activity In Vffm. Science 1990. 249:1157-l 160.

Bos TJ, MONTECL+RO FS, MIIXJNOBU F, BALL AR JR, CHANC CHW, N~SHIMURA T, VOGT PK: Efficient Transformation of Chicken Embryo Fiiroblascs by c-jun Requires Structural Modification in Coding and Noncoding Sequences. Genes Dev 1990, 4~1677-1687.

Shows that deletion of the 27 amino-acids absent in v.Jun from the wild- type increases transformation by eightfold; further increase is obtained by deletion of the 3’ non-coding region.

45. CASTE- M, DANGY J.P, MECHTA F, HIRAI S.1. YANN M, SAMARLIT J, LV?.WLLY A, BRLJN G: Overexpression of Avian

or Mouse c-jun in Primary Chick Embryo Fibroblasts Con- fers a Partially Transformed Phenotype. Oncugene 1990, 5:1541-1547.

46. SUZUKI T, HA~HIMOTO Y. OKLINO H, SATO H, NISHINA H, IBA H: High-level Expression of Human c-jun Gene Causes Cellular Transformation of Chicken Embryo Fibrobiasts. J Cancer Res 1991, 82:5&64.

47. BAICHWAL VR, TJ~AN R Control of c-Jun Activity by lnterac- . . tion of a Cell-Specific Inhibitor with Regulatory Domain d:

Differences between v- and c-Jun. Cell 1990. 63:815+25. Following the initial studies of Bohmann and Tjian [48] the authors show that the amino-terminal deletion present in v,lun is essential for negative regulation of the Al transactivation domain in HeIa, but not in F9. HepG2 or Dnxpbila Schneider cells. Negative regulation can be relieved by transfection of excess c.Jun but only marginally by co- transfection of c.Jun and c-Fos.

48. BOHMANN D, TJ~ R: Biochemical Analysis of Transcriptional Activation by Jun: Differential Activity of c- and v-Jun. Cell 1989, 59~709-717.

19. NISHINA H. SATO H. SUZUKI T. SATO M, &A H: Isolation and Characterization of fru-2, an Additional Member of the fos gene Family. Proc Nafl Acud Sci USA 1990, 87:3619-3623.

50. CHILI R. A&GEL P. KAREN M: Jun-B Differs in its Biological . Properties from, and is a Negative Regulator of, c-jun Cell

1989. 59:97+986. The study shows that c-Jun and JunB diBer in their transactivation properties. The second depen& on co-operative interaction between adjacent hound factors. Excess JunB also inhibits transactition by c.Jun.

51. SCH~TTTE J, VVULET J, NALI M. SECAL S, FED~RKO J, MINNA J: . Jun-/3 Inhibits and c.Jos Stimulates the Transforming and

Trans.activating Activities of c-jun Cell 1989, 59:987-997. This study shows that JunB is less efficient than c-Jun in cell transformation and that it may be a negative regulator of c-Jun.

52 iMECHTA F, PIN= J. HIRAI S-I. YANIV M: Stimu~tion of Protein Kinase A Mediated Signal Transduction Pathways Shows Three Modes of Response Among Serum Inducible Genes. New Biol 1989, 1:297-304.

53. BAR~L DP. SHENG M, IAU LF. GREENBERG ME: Growth Factors and Membrane Depolarization Activate Distinct Programs of Early Response Gene Expression: Dissociation of Fos and Jun Induction. Genes Dal 1989. 3:304-313.

54. SCHULE R, UME~ONO K, MANGE~SDIXI DJ, BO~AW J, WESLF( . PIE J, EVANS RM: Jun-Fos and Receptors for Vitamins A and

D Recognize a Common Response Element in the Human Osteocalcin Gene. Cell 1990, 61:497-5&i.

Demonstrates that the retinoic acid and vitamin response of the os- teocakin gene includes a binding site for the Jun/Fos heterodimer. Both basal and hormone-induced transcription are inhibited by excess Jun/Fos. Suggests that AF-1 can stimulate growth and suppress the dif- ferentiated phenotype

55. GALJB MP, BEUARD M, SCHEUER 1, CHA~~BON P, S~NE-CO&I P: . . Activation of the Ovalbumin Gene by the Estrogen Recep-

tor Involves the Fos-Jun Complex. Cell 19!X, 63:1267-1276. Estrogen activation of the ovalbumin promoter involves the sequence TGGGTCAhalf palindromic ERE, a sequence that also mediates induction by phorbol esters through binding of c.Jun and c-Fos. Co-opera- tivity in transcriptional activation is observed between the receptor and c-Jun or c-Fos. The authors suggest that the receptor directly interacts with Jun/Fos and that its DNA-binding domain is dispensable for this interaction,

56. DLA~IOND Ml, MINER JN, YOSH~NAGA SK, YA~IAMOTO KR: . . Transcription Factor Interactions: Selectors of Positive or

Negative Regulation from a Single DNA Element. Science 1990, 249:126&1272.

Delines a composite GRE that can bind both API and GR ln the pres ence of c.Jun the receptor co-operates in transcriptional activation. On the contrary, in the presence of c-Jun and excess c-Fos it inhibits AP-1 transcriptional activation. Jun but not Fos forms complexes with the receptor.

Nuclear ontxwenes Ghvsdael and Yaniv 491

57. JONAT C, RAHMS~JORF HJ, P,UK KK, CATO ACB, GEBEL S, POWA . . H, HERRUCH P: Antitumor Promotion and Anti-inflammation:

Down-Modulation of API (Fos/Jun) Activity by Glucocor- ticoid Hormone. Cell 1990, 62:1189-1204.

The first in a series of papers dealing with the crosstalk between glucoconicoid hormone receptor and AP1. These observations clarify the molecular mechanism of the anti-inilammatory effect of glucocorticoids by showing that dexamethasone inhibits the phorbol ester-induced syn thesis of coilagenase. Shows that transrepression occurs at a lower hormone concentration than transactivation.

58. LIJCIBELL~ FC, S~AI-ER EP, Jooss KU, BEATO M, M~JUER R Mu- . . tuaI Transrepression of Fos and Glucocotticoid Receptor:

Involvement of a Functional Domain in Fos which is Absent in fosB. EMBO J 1990, 9:2827-2834.

Demonstrates inhibition of transcriptional activity of GR by c-Fos but not by FosB, and the reversal inhibition of Fosmediated transactivation of AI-l-dependent transcription. Furthermore, repression of the serum responsive element by Fos is abolished by GR Transrepression involves sequences in the amino-terminal part of c-Fos without any pre- viously defined biochemical function. The central DNA-binding domain is crucial in the receptor. There is no evidence for complex formation between Fos and GR.

59. YANGYEN m. cHAhmARD Jc, SUN & SMEAL T, ScHMlnT 17, . . DROUIN J, KAIUN M: Transcriptional Interference Between

c-Jun and the Glucoconicoid Receptor - Mutual Inbibi- tion of DNA Binding Due to Direct Protein Interaction. Cell 1990, 62:1205-1215.

Shows that GCR inhibition of AP.1 activity can be overcome by excess c.Jun. Experiments with Jun-GHFI chimera show that inhibition is not due to ‘squelching’ and that intact GR DNA-binding activity is essential for inhibition. Gel shift assay shows convincingIy that Jun inhibits specific GR DNA.binding; the reverse is less convincing.

&I. ScHlXE R. RANCARAJAN P, KLI’AVER S, hNSOhlE LJ. BOLADO J, . . YANG N, VERMA IM, EVANS RM: Functional Antagonism Be-

tween Oncoprotein C-Jun and tire Glucocorticoid Recep- tor. Cell 1990, 62:1217-1226.

Demonstrates that the DNA-binding domain of the receptor is essen tial for the inhibition of AP.1 activity, while the leucine repeat domain of c.Jun is crucial and probably sufficient for receptor inhibition. Also demonstrates that c.Jun inhibits GRGRE complex formation.

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BIEDENKA~P H, BORGMEYER U, SIPPEL AE, KIIMPNAUER, KH: Vi- ral my6 Oncogene Encodes a Sequence-speci6c DNA-binding Activity. Nature 1988, 3353835-837. ._.

This report is me hrst demonstration mat Myb binds specihc DNA sequences

Douw V, SP~ROU G. YAIW M: Unregulated Expression of c-Jun or c-Fos Proteins but not JunD Inhibits Oestrogen Receptor Activity in Human Breast Cancer Derived CeIIs. EMBO J 1991, in press.

SHEN-ONG GLC: The my6 oncogene. Bicxbetn Bioplq~s AC&J 1990, 1032:3952.

COLE MD: The my6 and myc Nuclear Oncogenes as Tran- scriptional Activators. Curr @in Cell Biol 1990, 2:502-508.

MIZUGUSHI G, NAKAG~SHI H, NAGAAE T, NOMURA N, DATE T, UENO Y, ISHII S: DNA-binding Activity and Transcriptional Activator Function of the Human B-myb Protein Compared with c-Myb. J Biol Cbem 199il, 265:92&X9284.

66. . .

NESS SA, MARKNEIL A, GRAF T: The v-myb Oncogene Rod- uct Bids to and Activates the Promyelocyte-specific mim-1 Gene. Cell 1989, 59:11151125.

Reports the identification by cDNA library ditferenrial screening of a v-mfireguiated gene in transformed myelobiasts and the demonstration of the direct activation of the gene by Myb through speciIic DNA sequences.

67. HOWE KM, REAKES CFI WATSON RJ: Characterization of the . Sequence-specitic Interaction of Mouse c-my6 Protein with

DNA EMBO J 1990, 9:161-169.

The dissection of the role of Rl, IQ, and R3 repeats of Myb in DNA- binding; the study also provides experimental evidence that Myb binds DNA as a monomer.

68. FWWTON J, I+UIX A, GIBSON TJ, GIWF T: DNA-binding Do- main Ancestty. Nalrrre 1989, 342:134.

69. SAWMAR P, MURALI R, REDDY P: Role of Ttyptophan Repeats . sod Flanking Amino-acids In Myb-DNA Interactions. Proc

Nat1 Acud Sci USA 1990, 87:8452+3456. A mutational analysis of Myb DNA-binding domain which provides experimental support for the existence of an HI3-I structure In the Myb DNA.binding domain.

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FRAMPTON J, GIBBON TJ, NESS SA, WDERLEIN G, GRAF T: Ro- posed Structure for the DNA-binding Domain of the Myb Oncoprotein Based on Model Building and Mutational Anal- ysis. EMBO J 1991, in press.

An extensive murational analysis of Myb binding activity, transcriptionai activity, and biological Function in conjunction with molecuIar mod- eUing to support a H-T-H structure for the Myb DNA-binding domain, similar to that of homeodomains.

71. SAXURA MC, KANEI-1s~ C, NAGASE T, NAKAGOSHI H, GONDA IJ: Delineation of Three Functional Domains of the Tran- scriptional Activator Encoded by the c-myb Roto-oncogene. Prcx Nati Acad Sci USA 1989, 86~5758-5762.

72. LUNCHER BE, CHRISTENSON E, LITCHREID DW, KREBS EG, . ElsENhlAN RN: Myb DNA-binding Inhibited by PhosphoryIa-

tion at a Site Deleted During Oncogenic Activation. Nature 1990, 344:517-522.

The study shows Myb to be phosphor-y&d on two adjacent serine residues by casein kinase II. with the subsequent loss of affinity for specific DNA sequences.

73. KIIMPNAUER KH, ARNOID H, BIEDENKAPP H: Activation of Tran- scription by v-myh Evidence for Two Diiferent Mecha- nisms. Genes Derj 1989, 3:1582-1589.

74. WERER BL, WESTIN EH. CIARICE MF: Differentiation of Mouse Etythroleukemia CeIIs Enhanced by Alternatively Spliced c-my6 mRNA Science 1990, 249:1291-1293.

75. MURRI C, SCHONIEBER MCCAW P. BALTIMORE D: A New DNA Binding and Dimerixation Motif in Immunogiobulin En- hancer Binding, Daughterless, MyoD, and myc Roteins. Cell 1989, 56:777-783.

76. GREC~R PD, SAWAIXXX M, ROEDER RG: The Adenovims Major . Late Transcription Factor USF is a Member of the HeIix-

Loop-Helix Group of Regulatory Roteins and Bids DNA as a Dimer. Genes Derl 1990, 4:173@1740.

The isolation of a cDNA for transcription factor USF. The deduced amino acid sequence predicts the presence of a BR-HLH-LR motif at the carboxyterminal which is required for both DNA-binding and homodimerization.

77. Hu Y, LUSCHER B, ADMON A, MERMOD N, TJW R Transcription . Factor AP-4 Contains Multiple Dimerixation Domains that

Regulate Dimer Speciiicity. Genes Deu 1990, 4:1741-1752. The molecular cloning of a cDNA for transcription factor AP-4. The deduced amino acid sequence predicts the presence of a BR-HLHLR motif at the carboxyl terminus of AP-4. The leucine repeat region is essential for homodimerization but fails to engage AP.4 in heterodimers with the El2 immunoglobulin-enhancer binding protein E12.

78. BLWXWEU TK, KREIZNER L, BLQXV~~D EM, EISENMAN RN, . . WEUQTRAUB H: Sequence-specific DNA-binding by the c-Myc

Protein. Science 1990, 250:11491151. The use of ampikicstion of selected bound sequences by a bacteriaIIy expressed carboxy-terminal fragment of Myc. The bound sequences were ail found to contain a centraI CACGTG core sequence.

79. STONE J, DE LANGE T, RMcslru G, JAKOBOVITX F, BISHOP JM, VAI&IUS HE, LEE W: DeIinition of Regions In Human c-myc that are InvoIved in Transformation and Nuclear LocaIixa- tion. Mel Cell Biol 1987, 7:1697-1709.


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. CROUCH DM, LANG C, GUIESPIE DAF: The L.e.ucine Zipper Domain of Avian c-Myc is Required for Transformation and Autoregulation. Oncogene 1990, 5683-689.

PENN b Brtoow MW, LIFER EM, fn-ruzwoo~ T, MORGENS~XRN JP, EVAN GI, &E WF, LID H: Domains of Human c-myc Pro- tein Required for Autosuppression and Cooperation with ru.s are Overlapping. Mel cell Bid 1990, 10:4%1-59&j.

E-o PJ: A Small Deletion in the Carboxy terminus of the Vii myc Gene Renders the Viis MC29 Partially Transformation-Defective in Avian Fiiroblasts. Vimlogy 1989, 168:256266.

USHER B, EISENMAN RN New Light on Myc and Myb. Part 1. Myc. Genes L&J 1990, 4:2025-2035.

EUERS M, SCHIRM S, BISHOP JM: The myc Protein Activates Transcription of the a-Prothymosin Gene. EMBO J 1991. 10:13$141.

Reports the use of chimera composed of the hormone-binding domain of the estrogen receptor fused to Myc to demonstrate that Myc is sti- ficient to elicit re-entry into and progression through, the cell cycle of rodent primary cells. Activation of Myc by estrogen treatment of trans. fected cells leads to the rapid transcriptional actimtion of the a-prothymosin gene.

85. KIERAN M, BLANK V, LOCEXT F, VANDERKERCN~OVE J, L~‘I-IIPEICH . . F, II BAU 0, URBAN M, KOUIU~XY P, BAUERLE PA, ISRAEL A:

The DNA-biding Subunit of NF-xB is Identical to Factor KBFl and Homologous to the rel Oncogene Roduct. Cell 1990 62:1007-1018.

@scribes the cloning of a cDNA encoding the precursor form of KBF- 1 and its homology in the DNA-binding and dimerization domains to ref and &sal This precursor fails to bind specific DNA sequences but binding activity is unmasked following carboxy-terminal truncation. In these conditions, KBF-1 binds to DNA either as a homcdimer or as heterodimers with v-Rel or the 50 or 65 kD subunits of NFxB.

86. GHCXH S, G~FFORD AM, RMERE L, TEMP~T P, Now GP, . . BAL~ORE D: Cloning of the p50 DNA-binding Subunit of

NF-%B: Homology to ref and dotsaL Cell 1990, 62:1019-1029.

Reports the purification and partial sequencing of the 50 and 65kD subunit of NF-xB and the isolation of a cDNA encoding a precursor form the 50kD DNA-binding subunit of NF-xB and its kinship to rel and dorsal The precursor form fails to bind XB motifs but DNA-binding activity is unmasked following carboxy-tetminal truncation. The 65 kD subunit of NF-XB appears homologous to members of the Rel family. 87. B~WRD DW WAIKER NH, D~ERRE S, SISTA P, MOUTOR J4 . . DEVON EP, PFEFFER NJ, HANNINK M, GREENE WC: The v-rel

Oncogene Encodes a xB Enhancer Siding Protein that Inhibits NF-XB Function. Cell 1990, 63:803+X4.

Describes the identification of four proteins including NF-xB and c-Rel, related to one another and able to bind to a xB motif in T cells. Furthermore, reports that v-Rel also binds to KB motifs and inhibits NFxB-mediated actiwtion of early T-cell response genes. 88.

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MORRISON LE, KABRUN N, MUDRI S, H.4w.t.w MJ, E-0 PJ: Viral rel and Cellular rel Associate with Cellular Proteins in Transformed and Normal Cells. Oncogene 1989, 4:677-683. DAVIS N, BARGMANN W, m M, BOSE H: Avian Reticulo- endotheliosis Virus-Transformed Lymphoid Cells Contain Multiple p~59~-“t Complexes. / Virof 1990, 64:58&591. MOUTOR J, WALKER W, DOERRE S, BALLARD DW, GREENE WC: NF-xB: a Family of Inducible and Differentially Expressed Enhancer-binding Proteins in Human T cells. Proc Nufl Acad Sci C&4 1990. 87:1002E&10032. KhMENS J, RIG HARLXON P, Mosws G, BRENT R, GI~MOIIE T: Oncogenic Transformation by v-Rel Requires an Amino-terminal Activation Domain. hlol Cell Biol 1990, 10:2840-2847. GILMORE TD, TEhUN HM: V-rel Oncoproteins in the Nucleus and in the Cytoplasm Transform Chicken Spleen Cells. J Viral 1988, 62:703-714.

J Ghysdael, Section de Biologie, Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France. M Yaniv. Epartement des Biotechnologies, lnstitut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.

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