DNA Sequence-/. DNA Sequencing and Mapping, Vol. 2, pp. 41 1-41 4 Reprints available directly from the publisher Photocopying permitted by license only
0 1992 Harwood Academic Publishers GmbH Printed in the United Kingdom
SHORT COMMUNICATION
Nucleotide sequence of bovine interleukin-6 cDNA L. DROOGMANS', I . CLUDTS', Y. CLEUTER', R. KETTMANN2 and A. BURNY'.'
' ' Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Laboratoire de Chimie Biologique, Universite Libre de Bruxelles, 67, Rue des Chevaux, 1640 Rhode-St-Genese, Belgium. Telefax (+32) 2 650 9999, Telephone (+32) 2 650 9826, Facultes Agronomiques de Gembloux, UER Biologie Moleculaire, 7 3, Avenue Marechal Juin, 5030 Gembloux, Belgium
EMBL Data Library Accession No.: X57317
We report the cloning of bovine interleukin-6 (11-6) cDNA. The clone was isolated from a bovine-leukemia virus (B1V)induced B cell-lymphosarcoma cDNA library cloned in the bacteriophage lambda g t l l . The cDNA encodes a full length 11-6 protein made of 208 amino acids with 65, 53, 42 and 42% homology to published sequences of porcine, human, mouse and rat 11-6, respectively. The significance of 11-6 expression in a BLV-induced tumor i s briefly discussed.
leukemia virus (BLV) is closely related to HTLV-I and induces B cell malignancies in cattle (for a review see Burny et a/., 1987). Since IL-6 plays a key role i n B cell growth and differentiation it i s important to determine whether BLV infection triggers IL-6 gene expression. Here w e report the nucleotide sequence of a bovine IL-6 cDNA. This was isolated from a BLVinduced B cell lymphosarcoma c D N A library constructed i n lambda g t l 1 (Willems eta/., 1992). The library was screened using a human probe (Haegeman eta/., 1986) under low stringency conditions. Fifteen clones (of 500,000 screened) were isolated and the longest insert was subcloned in the Eco RI site of pUC18 for sequencing (clone plL6B2). This clone (Fig. 1) encodes the full length bovine IL-6 protein as determined by comparison to the human, murine, rat and porcine cDNAs (Hirano et a/., 1986; Van Snick et a/., 1988; Northemann et a/., 1989; Richards et a/.,1991 ). The 1108 base pairs (bp) c D N A shows a 5 ' untranslated region of 42 bp, an open reading frame of 624 bp encoding a protein of 208 amino-acids followed by a 426 b p non-coding region and a polyA tract. A putative N-linked glycosylation site of the protein (Asn-X-Sernhr) i s found at position 38. By analogy with human and niurine proteins, the presumed cleavage site between signal and mature sequences i s located around amino-acids 26-30. At the nucleotide level, the bovine IL-6 cDNA shows 83% homology to porcine, 76% to human and 65% to mouse and rat IL-6 cDNAs. The protein shows 65, 53, 42 and 42% homology to the por-
KEY WORDS: bovine leukemia virus, cDNA, cytokine, interleukin
Interleukin-6 (IL-6) i s a multifunctional cytokine produced by a wide variety of cell types. One of the target cells for this cytokine is the B cell: IL-6 stimulates activated B cells to produce immunoglobulins and induces growth of hybridomas, plasmacytomas and Epstein-Barr virus (EBV)-immortalized B lymphoblastoid cells (for a review see Van Snick, 1990). Freeman et a/.(1989) reported IL-6 gene expression in activated B cells and constitutive expression in neoplastic B cells. The cytokine was therefore postulated t o function in an autocrine fashion to promote growth of B cell tumors. Viral infections induce IL-6 expression i n fibroblasts (Sehgal eta/., 1988). Also, EBV-induced lymphoblastoid cell lines produce IL-6 which was identified as an autocrine growth factor for these cells (Tosato et a/., 1990). Recently, it has been reported that human T cell lymphotropic virus type I (HTLV-I)-infected T cells produce IL-6 whereas normal T cells do not (Villiger eta/., 1991). Bovine Address correspondence to: L. Droogmans.
41 1
Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
41 2
1 1 4 52 18 94 32 136 46 178 60 220 74 262 a8 304 102 346 116 388 130 430 144 472 158 514 172 556 186 598 200 640 686 742 798 854 910 966 1022 1078
L. DROOCMANS ET AL
M
N S AAC TCC S L G TCC CTG GGG P G P CCG GGT CCC G R L GGC AGA CTA I K R ATT AAG CGC I C E ATA TGT GAG L A E CTG GCA GAA D G C GAC GGA TGC I R T ATC AGA ACC D Y L GAC TAC CTC R D L AGG GAT TTG K Q K AAG CAA AAG T D L ACT GAC CTG K N A AAG AAC GCA F L Q TTC CTG CAG
CCAGGAACGAAAGAGAGCTCCATCTGCCCTCCAGGAACAGCT ATG
R F T S A F T P F A V CGC TTC ACA AGC GCC TTC ACT CCA TTC GCT GTC L L L V M T S A F P T CTG CTC CTG GTG ATG ACT TCT GCT TTC CCT ACC L G E D F K N * D T T P CTG GGA GAA GAT TTC AAA AAT GAC ACC ACC CCA L L T T P E K T E A L CTT CTG ACC ACT CCA GAG AAA ACC GAA GCT CTC M V D K I S A U R K E ATG GTC GAC AAA ATC TCT GCA ATG AGA AAG GAG K N D E C E S S K E T AAG AAT GAT GAG TGT GAA AGC AGC AAG GAG ACA N K L N L P K U E E K AAT AAG CTG AAT CTT CCA AAA ATG GAG GAA AAG F Q S G F N Q A I C L TTC CAA TCT GGG TTC AAT CAG GCG ATT TGC TTG T A G L L E Y Q I Y L ACT GCT GGT CTT CTG GAG TAT CAG ATA TAC CTG Q N E Y E G N Q E N V CAG AAC GAG TAT GAG GGA AAT CAG GAA AAT GTC R K N I R T L I Q I L AGG AAA AAT ATC AGA ACA CTG ATC CAG ATC CTG I A D L I T T P A T N ATC GCA GAT CTA ATA ACC ACT CCA GCC ACA AAC L E K M Q S S N E W V CTG GAG AAG ATG CAG TCT TCA AAC GAG TGG GTA K I I L I L R N L E N AAG ATT ATC CTC ATC CTG AGA AAC CTT GAG AAT F S L R A I R U K TTC AGC CTG AGA GCT ATT CGG ATG AAG TAG CTGGGGCTCCCATGAT TGTGGTAGTTCCTGGGCATTCCCTCCTCTGGTCAGARACCTGTCCACTGGGCACAC AACTTATGTTGTTCTCTATGAAGAACTAAAAGTATGAGCGTTAGGACACTATTTTA TCTTTAATTTATTGATATTTAAATATGTGATTTTGAGTTAATTTATATACATGATA AGTATTTATATT'ITTATGAAGTGCCACTTGAAATATTTTATTTTATGTATTTGGTTTGAAA AAGTAACGTAAAAATGGCTATGTGGCTTGAATGTCCTTATTGTTTTGGAGACAAAT CATTTCTTGAAATGTGTAGGCTTACCTCAFAAAATTTGCTAACTTATGCATATTTT
MNSRF TSAFTPFAVSLGLLLVMTSAFPTPGPtGEDFKNLTTPGRLLLTTP . - ~ .~ ........ -~.___ . . ~ ~ ..... ~
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MNS TSTSAFGPVAFSLGLLLVLPAAFPAPVPXEDSKDVAAPHRQPLTSS 50 Human MNS LSTSAFSPVAFSLGLLLVPV\TAFPTFGRLPEDAKGDATSDWFTSP 50 Porcine
MKF LSARDFHPVAF L G I W L V T T T A F P T S Q V R R G D ~ E ~ P ~ P V Y T49 T S Murine MKF LSARDFQPVAF LGIWLLTATAFPTSQVRRGDFTEOTTHNRPVYTTS 49 Rat
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FQSGFNQAICLIRTTAGLLEYQIYLDYLQNEYEGN QENVRDLRKNIRTLI 151 B
FOSGFNEETCLVKIITGLLEFEVYLEYLQNRFESS EEOARAVOMSTKVLI 151 H F~SGFNQETC~~GCL~EFQIYLDYLQKEYESN 151 P YVTGYNQEICLLKISSGLLEYHSYLEYMKNNLKDNKKDKARVLQRDTETLI 150 M FQTGYNQEIGLLKICSGLLEFRFYLEFVKNNLQDNKKWARVIQSNTETLV 150 R
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QILKQKIADL ITT PATNTDLLEKMQSSNEWVKNAKIILILRNmNFL 198 B QFLQKKAKWLDAITTPDPTTNASLLTKLQAQNQWLQDM'ITHLILRSFKEFL 202 H QTLRQKGKNPDKATTPNFTl"AGLLDKLQSQNEh'MKNTKIIL1LRSLEDFL 202 P HIFNQEVKDLHKIVLPTPISNALLTDKLESQKEWLRTKTIQFIIXSLEEFL 201 M HIFKQEIKDSYKIVLPTPTSNALU4EKLESQKEWLRTKTIQLILKALEEFL 201 R
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QFSLRAIRMK QSSLRALRQM QFSLRAIRIM KVTLRSTRQT KtrrMRSTRQT
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208 212 212 211 211
B H P M R
Figure 2 Comparison of bovine, human, porcine, mouse and rat IL-6 amino-acid sequences. The sequences were aligned by pairs using the Microgenie software (Beckman). The five sequences were then aligned manually. Asterisks show highly conserved and points semi-conserved residues. The four invariant cysteines are underlined.
TAAAGGCATATTTATATTGTATTTATATAATGTTTAGGCTGTTTTTATAACm
g C T T C T T T T T T A A A G P
ACKNOWLEDGEMENTS Figure 1 cDNA sequence and derived amino-acid sequence of bovine IL-6. The sequence of the insert of clone plL6B2 is shown. The sequencing strategy was a combination of restriction fragments subcloning in M13 vectors and of primer walking. The sequence was determined on both strands. The Sequenase DNA sequencing kit (U.S. Biochemicals) was used. The polyadenylation signal is underlined. A potential N-linked glycosylation site found at position 38 is indicated by an asterisk.
cine, human, mouse and rat, respectively. Figure 2 shows the alignment of the sequences of the five IL-6 proteins. The most conserved region of the mature cytokine is found between amino-acids 68 and 126 of the bovine sequence. This region contains the four invariant cysteines most probably involved in maintaining the overall structure of the protein. The significance of IL-6 expression in a BLVinduced tumor has to be elucidated. Since this cytokine is a B cell growth and differentiation factor, the possibility exists that it could act as an autocrine factor for tumor cell growth. Also, the role of the different BLV components on IL-6 expression has to be clarified. In particular, we plan to determine whether the virus-encoded transactivator protein Tax is able the induce the IL-6 promoter.
We thank Dr I . Van Snick (Ludwig Institute for Cancer Research, Brussels Branch, Brussels) and Dr J. Content (Institut Pasteur du Brabant) for providing mouse and human IL-6 probes. W e thank R. Legas for technical assistance. R.K. and I.C. are, respectively, Directeur de Recherches and Aspirant of the FNRS (Fonds National Belge de la Recherche Scientifique). L.D. i s a fellow of the FNRS-Televie. We thank the Caisse Cenerale d'Epargne et de Retraite for financial support.
(Received 16th January 1992)
REFERENCES Burny, A,, Cleuter, Y., Kettmann, R., Mammerickx, M., Marbaix, G . , Portetelle, D., Van den' Broeke, A., Willems, L. and Thomas, R. (1987). Bovine leukemia: facts and hypotheses derived from the study of an infectious cancer. Cancer Surveys, 6 , 139-1 59. Freeman, G.J., Freedman, AS., Rabinowe, S.N., Segil, J.M., Horowitz, J., Rosen, K., Whitman, J.F. and Nadler, L.M. (1989). Interleukin-6 gene expression i n normal and neoplastic B cells. 1. C h . Invest. 83, 1512-1 51 8. Haegeman, G., Content, J., Volckaert, G., Derynck, R., Tavernier, J. and Fiers, W. (1986). Structural analysis of the
Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
BOVINE IL-6 SEQUENCE
sequence coding for an inducible 26-kDa protein in human fibroblasts. Eur. 1. Biochem. 159, 625-632. Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S.-I., Nakajima, K., Koyama, K., Iwamatsu, A., Tsunasawa, S., Sakiyama, F., Matsui, H., Takahara, Y., Taniguchi, T. and Kishimoto, T. (1986). Complementary D N A for a novel human interleuk'in (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324, 73-76. Northemann, W., Braciak, T.A., Hattori, M., Lee, F. and Fey, G.H. (1989). Structure of the rat interleukin 6 gene and its expression i n macrophage-derived cells. 1. Bio/. Chem. 264, 16072-1 6082. Richards, C.D. and Saklatvala, J. (1991 ). Molecular cloning and sequence of porcine interleukin 6 c D N A and expression of mRNA in synovial fibroblasts in vitro. Cytokine 3:269-276. Sehgal, P.B., Helfgott, D.C., Santhanam, U., Tatter, S.B., Clarick, R.H., Ghrayeb, J. and May, L.T. (1988). Regulation of the acute phase and immune responses in viral disease. Enhanced expression of the beta-2 interferon/hepatocyte-sti-
41 3
mulating factor/interleukin-6 gene in virus-infected human fibroblasts./. Exp. Med. 167, 1951-1956. Tosato, G., Tanner, I., Jones, K.D., Revel, M. and Pike, S.E. (1990). Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr Virus-immortalized B cells. /. Virol. 64,3033-3041. Van Snick, J. Cayphas, S., Szikora, J.-P., Renauld, J.-C., Van Roost, E., Boon, T. and Simpson, R.J. (1988). c D N A cloning of murine interleukin-HP1 : homology with human interleukin 6. f u r . J. Imrnunol. 18, 193-197. Van Snick, J. (1990). Interleukin-6, an overview. Annu. Rev. Immunol. 8,253-278. Villiger, P.M., Cronin, M.T., Amenomori, T., Wachrnan, W. and Lotz, M. (1991). IL-6 production by human T lymphocytes. Expression in HTLV-I infected but not in normal T cells. /. Immunol. 146,550-559. Willems, L., Kettmann, R., Chen, G., Portetelle, D., Burny, A. and Derse, D. (1992). A cyclic AMP-responsive DNA-binding protein (CREB2) i s a cellular transactivator of the bovine leukemia virus long terminal repeat. ]. Viral. in press.
0 1992 Harwood Academic Publishers GmbH Printed in the United Kingdom
SHORT COMMUNICATION
Nucleotide sequence of bovine interleukin-6 cDNA L. DROOGMANS', I . CLUDTS', Y. CLEUTER', R. KETTMANN2 and A. BURNY'.'
' ' Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
Laboratoire de Chimie Biologique, Universite Libre de Bruxelles, 67, Rue des Chevaux, 1640 Rhode-St-Genese, Belgium. Telefax (+32) 2 650 9999, Telephone (+32) 2 650 9826, Facultes Agronomiques de Gembloux, UER Biologie Moleculaire, 7 3, Avenue Marechal Juin, 5030 Gembloux, Belgium
EMBL Data Library Accession No.: X57317
We report the cloning of bovine interleukin-6 (11-6) cDNA. The clone was isolated from a bovine-leukemia virus (B1V)induced B cell-lymphosarcoma cDNA library cloned in the bacteriophage lambda g t l l . The cDNA encodes a full length 11-6 protein made of 208 amino acids with 65, 53, 42 and 42% homology to published sequences of porcine, human, mouse and rat 11-6, respectively. The significance of 11-6 expression in a BLV-induced tumor i s briefly discussed.
leukemia virus (BLV) is closely related to HTLV-I and induces B cell malignancies in cattle (for a review see Burny et a/., 1987). Since IL-6 plays a key role i n B cell growth and differentiation it i s important to determine whether BLV infection triggers IL-6 gene expression. Here w e report the nucleotide sequence of a bovine IL-6 cDNA. This was isolated from a BLVinduced B cell lymphosarcoma c D N A library constructed i n lambda g t l 1 (Willems eta/., 1992). The library was screened using a human probe (Haegeman eta/., 1986) under low stringency conditions. Fifteen clones (of 500,000 screened) were isolated and the longest insert was subcloned in the Eco RI site of pUC18 for sequencing (clone plL6B2). This clone (Fig. 1) encodes the full length bovine IL-6 protein as determined by comparison to the human, murine, rat and porcine cDNAs (Hirano et a/., 1986; Van Snick et a/., 1988; Northemann et a/., 1989; Richards et a/.,1991 ). The 1108 base pairs (bp) c D N A shows a 5 ' untranslated region of 42 bp, an open reading frame of 624 bp encoding a protein of 208 amino-acids followed by a 426 b p non-coding region and a polyA tract. A putative N-linked glycosylation site of the protein (Asn-X-Sernhr) i s found at position 38. By analogy with human and niurine proteins, the presumed cleavage site between signal and mature sequences i s located around amino-acids 26-30. At the nucleotide level, the bovine IL-6 cDNA shows 83% homology to porcine, 76% to human and 65% to mouse and rat IL-6 cDNAs. The protein shows 65, 53, 42 and 42% homology to the por-
KEY WORDS: bovine leukemia virus, cDNA, cytokine, interleukin
Interleukin-6 (IL-6) i s a multifunctional cytokine produced by a wide variety of cell types. One of the target cells for this cytokine is the B cell: IL-6 stimulates activated B cells to produce immunoglobulins and induces growth of hybridomas, plasmacytomas and Epstein-Barr virus (EBV)-immortalized B lymphoblastoid cells (for a review see Van Snick, 1990). Freeman et a/.(1989) reported IL-6 gene expression in activated B cells and constitutive expression in neoplastic B cells. The cytokine was therefore postulated t o function in an autocrine fashion to promote growth of B cell tumors. Viral infections induce IL-6 expression i n fibroblasts (Sehgal eta/., 1988). Also, EBV-induced lymphoblastoid cell lines produce IL-6 which was identified as an autocrine growth factor for these cells (Tosato et a/., 1990). Recently, it has been reported that human T cell lymphotropic virus type I (HTLV-I)-infected T cells produce IL-6 whereas normal T cells do not (Villiger eta/., 1991). Bovine Address correspondence to: L. Droogmans.
41 1
Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
41 2
1 1 4 52 18 94 32 136 46 178 60 220 74 262 a8 304 102 346 116 388 130 430 144 472 158 514 172 556 186 598 200 640 686 742 798 854 910 966 1022 1078
L. DROOCMANS ET AL
M
N S AAC TCC S L G TCC CTG GGG P G P CCG GGT CCC G R L GGC AGA CTA I K R ATT AAG CGC I C E ATA TGT GAG L A E CTG GCA GAA D G C GAC GGA TGC I R T ATC AGA ACC D Y L GAC TAC CTC R D L AGG GAT TTG K Q K AAG CAA AAG T D L ACT GAC CTG K N A AAG AAC GCA F L Q TTC CTG CAG
CCAGGAACGAAAGAGAGCTCCATCTGCCCTCCAGGAACAGCT ATG
R F T S A F T P F A V CGC TTC ACA AGC GCC TTC ACT CCA TTC GCT GTC L L L V M T S A F P T CTG CTC CTG GTG ATG ACT TCT GCT TTC CCT ACC L G E D F K N * D T T P CTG GGA GAA GAT TTC AAA AAT GAC ACC ACC CCA L L T T P E K T E A L CTT CTG ACC ACT CCA GAG AAA ACC GAA GCT CTC M V D K I S A U R K E ATG GTC GAC AAA ATC TCT GCA ATG AGA AAG GAG K N D E C E S S K E T AAG AAT GAT GAG TGT GAA AGC AGC AAG GAG ACA N K L N L P K U E E K AAT AAG CTG AAT CTT CCA AAA ATG GAG GAA AAG F Q S G F N Q A I C L TTC CAA TCT GGG TTC AAT CAG GCG ATT TGC TTG T A G L L E Y Q I Y L ACT GCT GGT CTT CTG GAG TAT CAG ATA TAC CTG Q N E Y E G N Q E N V CAG AAC GAG TAT GAG GGA AAT CAG GAA AAT GTC R K N I R T L I Q I L AGG AAA AAT ATC AGA ACA CTG ATC CAG ATC CTG I A D L I T T P A T N ATC GCA GAT CTA ATA ACC ACT CCA GCC ACA AAC L E K M Q S S N E W V CTG GAG AAG ATG CAG TCT TCA AAC GAG TGG GTA K I I L I L R N L E N AAG ATT ATC CTC ATC CTG AGA AAC CTT GAG AAT F S L R A I R U K TTC AGC CTG AGA GCT ATT CGG ATG AAG TAG CTGGGGCTCCCATGAT TGTGGTAGTTCCTGGGCATTCCCTCCTCTGGTCAGARACCTGTCCACTGGGCACAC AACTTATGTTGTTCTCTATGAAGAACTAAAAGTATGAGCGTTAGGACACTATTTTA TCTTTAATTTATTGATATTTAAATATGTGATTTTGAGTTAATTTATATACATGATA AGTATTTATATT'ITTATGAAGTGCCACTTGAAATATTTTATTTTATGTATTTGGTTTGAAA AAGTAACGTAAAAATGGCTATGTGGCTTGAATGTCCTTATTGTTTTGGAGACAAAT CATTTCTTGAAATGTGTAGGCTTACCTCAFAAAATTTGCTAACTTATGCATATTTT
MNSRF TSAFTPFAVSLGLLLVMTSAFPTPGPtGEDFKNLTTPGRLLLTTP . - ~ .~ ........ -~.___ . . ~ ~ ..... ~
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MKF LSARDFHPVAF L G I W L V T T T A F P T S Q V R R G D ~ E ~ P ~ P V Y T49 T S Murine MKF LSARDFQPVAF LGIWLLTATAFPTSQVRRGDFTEOTTHNRPVYTTS 49 Rat
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B H P M R
Figure 2 Comparison of bovine, human, porcine, mouse and rat IL-6 amino-acid sequences. The sequences were aligned by pairs using the Microgenie software (Beckman). The five sequences were then aligned manually. Asterisks show highly conserved and points semi-conserved residues. The four invariant cysteines are underlined.
TAAAGGCATATTTATATTGTATTTATATAATGTTTAGGCTGTTTTTATAACm
g C T T C T T T T T T A A A G P
ACKNOWLEDGEMENTS Figure 1 cDNA sequence and derived amino-acid sequence of bovine IL-6. The sequence of the insert of clone plL6B2 is shown. The sequencing strategy was a combination of restriction fragments subcloning in M13 vectors and of primer walking. The sequence was determined on both strands. The Sequenase DNA sequencing kit (U.S. Biochemicals) was used. The polyadenylation signal is underlined. A potential N-linked glycosylation site found at position 38 is indicated by an asterisk.
cine, human, mouse and rat, respectively. Figure 2 shows the alignment of the sequences of the five IL-6 proteins. The most conserved region of the mature cytokine is found between amino-acids 68 and 126 of the bovine sequence. This region contains the four invariant cysteines most probably involved in maintaining the overall structure of the protein. The significance of IL-6 expression in a BLVinduced tumor has to be elucidated. Since this cytokine is a B cell growth and differentiation factor, the possibility exists that it could act as an autocrine factor for tumor cell growth. Also, the role of the different BLV components on IL-6 expression has to be clarified. In particular, we plan to determine whether the virus-encoded transactivator protein Tax is able the induce the IL-6 promoter.
We thank Dr I . Van Snick (Ludwig Institute for Cancer Research, Brussels Branch, Brussels) and Dr J. Content (Institut Pasteur du Brabant) for providing mouse and human IL-6 probes. W e thank R. Legas for technical assistance. R.K. and I.C. are, respectively, Directeur de Recherches and Aspirant of the FNRS (Fonds National Belge de la Recherche Scientifique). L.D. i s a fellow of the FNRS-Televie. We thank the Caisse Cenerale d'Epargne et de Retraite for financial support.
(Received 16th January 1992)
REFERENCES Burny, A,, Cleuter, Y., Kettmann, R., Mammerickx, M., Marbaix, G . , Portetelle, D., Van den' Broeke, A., Willems, L. and Thomas, R. (1987). Bovine leukemia: facts and hypotheses derived from the study of an infectious cancer. Cancer Surveys, 6 , 139-1 59. Freeman, G.J., Freedman, AS., Rabinowe, S.N., Segil, J.M., Horowitz, J., Rosen, K., Whitman, J.F. and Nadler, L.M. (1989). Interleukin-6 gene expression i n normal and neoplastic B cells. 1. C h . Invest. 83, 1512-1 51 8. Haegeman, G., Content, J., Volckaert, G., Derynck, R., Tavernier, J. and Fiers, W. (1986). Structural analysis of the
Mitochondrial DNA Downloaded from informahealthcare.com by V U L Periodicals Rec on 12/28/14 For personal use only.
BOVINE IL-6 SEQUENCE
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