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Rel/NF-Kb Transcription Factors and Ikb Inhibitors: Evolution from a Unique Common Ancestor

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Rel/NF-Kb Transcription Factors and Ikb Inhibitors: Evolution from a Unique Common Ancestor Oncogene (1997) 15, 2965 ± 2974 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Rel/NF-kB transcription factors and IkB inhibitors: Evolution from a unique common ancestor Christelle Huguet1, Pascale Crepieux2 and Vincent Laudet2 1Laboratoire de reÂgulation des processus invasifs, de l'angiogeneÁse et de l'apoptose, EP560; 2Laboratoire des meÂcanismes du deÂveloppement et de la canceÂrisation, UMR319, IFR3 Institut de Biologie de Lille, 1 rue du Professeur Calmette, 59021 Lille, France From the sequences of Rel/NF-kB and IkB proteins, we 1995; Verma et al., 1995). Some of the Rel/NF-kB constructed an alignment of their Rel Homology Domain proteins, namely cRel, RelA, RelB/IRel, Dorsal and (RHD) and ankyrin repeat domain. Using this align- Dif (the `ready-to-use' members), contain a transacti- ment, we performed tree reconstruction with both vating domain in their C-terminal half (for references distance matrix and parsimony analysis and estimated see Table 1). The others, the p50 and p52 subunits, are the branching robustness using bootstrap resampling proteolytically maturated from the precursor proteins methods. We de®ned four subfamilies of Rel/NF-kB NF-kB1 (p105) and NF-kB2 (p100) respectively and transcription factors: (i) cRel, RelA, RelB, Dorsal and are devoid of transactivating domain (Table 1). Relish, Dif; (ii) NF-kB1 and NF-kB2; (iii) Relish and (iv) NF- a gene structurally related to NF-kB genes, has been AT factors, the most divergent members. Subfamilies I recently cloned in Drosophila (Dushay et al., 1996). and II are clustered together whereas Relish diverged Members of the Rel-NF-kB family bind DNA as homo earlier than other Rel/NF-kB proteins. Three subfamilies or heterodimers and recognize the consensus decameric of IkB inhibitors were also de®ned: (i) NF-kB1 and NF- sequence 5'-GGGPuNNPyPyCC-3' which is named kB kB2; (ii) close to subfamily I, the short IkB proteins site. Dierent kB sites among gene promoters are IkBa,IkBband Bcl-3; (iii) Relish that diverged earlier bound with dierent anities by the various dimers than other IkB inhibitors. Our de®nition of groups and which therefore bind certain target genes preferentially subfamilies ®ts to structural and functional features of (Chytil and Verdine, 1996; Miyamoto and Verma, the Rel/NF-kB and IkB proteins. We also showed that 1995; MuÈ ller et al., 1996). In addition, depending on ankyrin repeats of NF-kB1, NF-kB2 and Relish are the dimers, the transcription of the target gene is short IkB-speci®c ankyrin motifs. These proteins de®ning activated or repressed; for example RelA/p50, RelA/ a link between Rel/NF-kB and IkB families, we propose cRel, RelB/p50, RelB/p52 are potent transcriptional that all these factors evolved from a common ancestral activators, whereas p50/p50 or p52/p52 homodimers RHD-ankyrin structure within a unique superfamily, generally repress transcription (Siebenlist et al., 1994; explaining the speci®cities of interaction between the Verma et al., 1995). dierent Rel/NF-kB dimers and the various IkB The various Rel/NF-kB dimers are submitted to inhibitors. dierent regulations by inhibitors of the IkB family (Miyamoto and Verma, 1995). The IkB family is a Keywords: ankyrin repeat protein; rel homology subfamily of ankyrin repeat proteins including IkBa, domain; NF-AT; molecular phylogeny IkBb,IkBg, Bcl-3, NF-kB1 and NF-kB2. The NF-kB precursor proteins present ankyrin repeats in their C- terminal half thereby exhibiting IkB inhibitory func- tions (Siebenlist et al., 1994). The IkB proteins bind the Introduction various Rel/NF-kB dimers with dierent anities, and retain them in the cytoplasm (Miyamoto and Verma, Transcription factors represent key molecules that 1995). Activation of the Rel/NF-kB proteins requires convert signals received by the cell into activation or phosphorylation and subsequent degradation of the repression of genes that lead to cell responses such as IkB inhibitors, thus allowing the transcription complex proliferation, dierentiation or apoptosis. The Rel/NF- to translocate into the nucleus (Finco and Baldwin, kB transcription factors are involved in the immune 1995; Thanos and Maniatis, 1995; Verma et al., 1995). response, i.e. in immunoreceptor gene expression, Once in the nucleus, the Rel/NF-kB transcription cytokine and growth factor regulation, and also in factors will regulate the transcription of various target embryonic development and programmed cell death genes including their own genes in an autoregulatory (Baeuerle and Henkel, 1994; Huguet et al., 1994; loop, thus reconstituting the stocks of Rel/NF-kB Kabrun et al., 1990; Kopp and Ghosh, 1995). These proteins in the cytoplasm. Moreover, they will activate Rel/NF-kB proteins share a 300 amino acid N-terminal the transcription of their IkB inhibitors leading to the domain, named the Rel Homology Domain (RHD), production of new IkB proteins. The newly synthesized which harbors a DNA-binding region, a dimerization IkBa will terminate the activation of Rel/NF-kB domain, a nuclear localization signal and a region of factors by migrating into the nucleus and displacing interaction with inhibitory proteins of the IkB family the Rel/NF-kB dimers from the DNA. On the (Chytil and Verdine, 1996; Miyamoto and Verma, contrary, the newly synthesized IkBb will continue the activation by protecting the Rel/NF-kB dimers Correspondence: V Laudet from the inhibition of the newly synthesized IkBa Received 24 April 1997; revised 1 August 1997; accepted 1 August (Baeuerle and Baltimore, 1996; Gilmore et al., 1996; 1997 Miyamoto and Verma, 1995). Rel/NF-kBandIkBevolution CHuguetet al 2966 Table 1 Sequences used in this study. For each sequences, the Genbank code and the accession number, when dierent, were given as well as the reference. The sequences are given in the order of the distance trees (Figure 1 left panel) Gene species Databank accession Reference Rel/NF-kB Family Homo cRel HSRNAREL/X75042 (Brownell et al., 1989) Mus cRel MMCRELM/X15842 (Grumont and Gerondakis, 1989) Gallus cRel GSP68REL/X52193 (Capobianco et al., 1990) Meleagris cRel TKYREL09/K02455 (Wilhemsen et al., 1984) Viridae Rel ACRREL/K00555/X02759 (Wilhemsen et al., 1984) Xenopus Xrel2 XLREL2POR/Z49252 (Tannahill and Wardle, 1995) Homo RelA HUMP65NFKB/M62399 (Ruben et al., 1991) Mus RelA MUSNFKP65/M61909 (Nolan et al., 1991) Xenopus Xrel1 XELREL/M60785 (Kao and Hopwood, 1991) Gallus RelA CHKNFKB2/D13721 (Ikeda et al., 1993) Homo Irel HUMIRELA/M83221 (Ruben et al., 1992a) Mus RelB MUSRELB/M83380 (Ryseck et al., 1992) Xenopus RelB XLRELB/D63332 (Suzuki et al., 1995) Drosophila Dorsal DRODORSAL/M23702 (Steward, 1987) Drosophila Dif DRODIF/L29015 (Ip et al., 1993) Homo NF-kB1 HUMNFKB34/M55643/M37492 (Kieran et al., 1990) Mus NF-kB1 MUSTFDBS/M57999/M37732 (Ghosh et al., 1990) Gallus NF-kB1 CHKP105A/M86930 (Capobianco et al., 1992) Homo NF-kB2 S76638 (Bours et al., 1992) Gallus NF-kB2 U00111 (Sif and Gilmore, 1993) Drosophila Relish U62005 (Dushay et al., 1996) NF-AT Family Homo NF-AT3 HUMNFAT3A/L41066 (Hoey et al., 1995) Homo NF-AT4 HUMHFAT4A/L41067 (Hoey et al., 1995) Homo NF-ATx HSU14510/U14510 (Masuda et al., 1995) Homo NF-ATc HSU08015/U08015 (Northrop et al., 1994) Mus NF-ATp MMU02079/U02079 (McCarey et al., 1993) IkB Family Homo NF-kB1 HUMNFKB34/M55643/M37492 (Kieran et al., 1990) Mus NF-kB1 MUSTFDBS/M57999/M37732 (Ghosh et al., 1990) Gallus NF-kB1 CHKP105A/M86930 (Capobianco et al., 1992) Homo NF-kB2 S76638 (Bours et al., 1992) Gallus NF-kB2 U00111 (Sif and Gilmore, 1993) Drosophila Relish U62005 (Dushay et al., 1996) Homo IkBa HUMMAD3A/M69043 (Haskill et al., 1991) Sus IkBa SDECI6A/Z21968 (De Martin et al., 1993) Rattus IkBa RRRLIF1/X63594 (Tewari et al., 1992) Gallus IkBa CHKPP40 (Davis et al., 1991) Drosophila Cactus DROCACTUS/L04964 (Geisler et al., 1992) Mus IkBb MMU19799/U19799 (Thompson et al., 1995) Homo Bcl-3 HUMBCL3AA/M31732 (Ohno et al., 1990) Ankyrin Family Homo Ankyrin HUMANK/M28880 (Lambert et al., 1990) Mus Ankyrin 1 MMANK1AA/X69063 (Birkenmeier et al., 1993) Drosophila Ankyrin DROANKY/L35601 (Dubreuil and Yu, 1994) A large set of experimental data recently illustrated Results how sophisticated the relationships between the Rel/ NF-kB transcription factors and their IkB inhibitors Alignment of sequence of the Rel/NF-kB and IkB are: autoregulatory loops, proteins displaying both proteins the roles of transcription factor and inhibitor, various combinations of transcriptional and inhibitory part- In order to produce a complete list of all known full ners undergoing dierent regulations. In fact, the length sequences of the members of both the Rel/NF- combination of the Rel/NF-kB and IkB families kB and IkB families (Table 1), we performed several constitutes a powerful and tightly controlled path- searches in the Genbank and EMBL databases using way to respond to various stimuli and to mediate the FASTA program. Only complete cDNA sequences speci®c cell response. Therefore, it is important to were kept. Therefore, since we only found a 3' ¯anking understand how these two families of genes evolved region for the mouse Bcl-3 gene in the data banks and diversi®ed to reach such a level of speci®city and (accession number M90397) despite its cloning cited by autoregulation. To address this question, we studied Ito et al. (1994), it has not been included in this study. in parallel the molecular evolution of the Rel/NF-kB Thirty-seven sequences were retained in this analysis: and IkB proteins. This phylogenetical analysis 25 in the Rel/NF-kB family and 14 in the IkB family; allowed to de®ne the structure of the putative the NF-kB1, NF-kB2 and Relish sequences belong to ancestor genes and to propose an evolutionary both families. Three ankyrin genes (erythroid ankyrin model that clusters both families in a unique Rel/ or ankyrin 1) were chosen as an outgroup for the IkB NF-kB/IkB superfamily.
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