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J Virol. Mar 1996; 70(3): 1990–1999.
PMCID: PMC190028

The CREB, ATF-1, and ATF-2 transcription factors from bovine leukemia virus-infected B lymphocytes activate viral expression.


Efficient transcription and replication of the bovine leukemia virus (BLV) genome require both the viral long terminal repeat (LTR) and the virus-coded transcriptional activator Tax, which functions through a 21-bp sequence (Tax-responsive element [TxRE]) which is repeated three times within the LTR. Since Tax does not bind directly to DNA, host cell transcription factors play a central role in BLV expression. Electrophoretic mobility shift assays with nuclear extracts prepared with infected bovine B lymphocytes revealed five TxRE-specific complexes (C1, C2, C3, C4, and C5). Here, by using a UV-induced indirect labeling technique (UV cross-linking) in conjunction with mobility shift assays, eight major polypeptides of 31, 33, 42, 46, 51, 57, 87, and 119 kDa were identified within these five complexes. Immunoprecipitation experiments identified the 57- and 119-kDa proteins as cyclic AMP response element-binding (CREB) proteins, the 46- and 51-kDa proteins as activating transcription factor-1 (ATF-1), and the 87-kDa as protein ATF-2. All of these proteins (except the ATF-1 protein of 51 kDa) belong to the complex C1, which is the major complex identified in freshly isolated BLV-infected lymphocytes from cattle with persistent lymphocytosis. In transient-cotransfection experiments, these three transcription factors were able to activate LTR-directed gene expression in the presence of protein kinase A or Ca2+/calmodulin-dependent protein kinase IV. CREB protein, ATF-1, and ATF-2 thus appear to be the major transcription factors involved in the early stages of viral expression.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adam E, Kerkhofs P, Mammerickx M, Kettmann R, Burny A, Droogmans L, Willems L. Involvement of the cyclic AMP-responsive element binding protein in bovine leukemia virus expression in vivo. J Virol. 1994 Sep;68(9):5845–5853. [PMC free article] [PubMed]
  • Anderson MG, Dynan WS. Quantitative studies of the effect of HTLV-I Tax protein on CREB protein--DNA binding. Nucleic Acids Res. 1994 Aug 11;22(15):3194–3201. [PMC free article] [PubMed]
  • Armstrong AP, Franklin AA, Uittenbogaard MN, Giebler HA, Nyborg JK. Pleiotropic effect of the human T-cell leukemia virus Tax protein on the DNA binding activity of eukaryotic transcription factors. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7303–7307. [PMC free article] [PubMed]
  • Baliga V, Ferrer JF. Expression of the bovine leukemia virus and its internal antigen in blood lymphocytes. Proc Soc Exp Biol Med. 1977 Nov;156(2):388–391. [PubMed]
  • Baranger AM, Palmer CR, Hamm MK, Giebler HA, Brauweiler A, Nyborg JK, Schepartz A. Mechanism of DNA-binding enhancement by the human T-cell leukaemia virus transactivator Tax. Nature. 1995 Aug 17;376(6541):606–608. [PubMed]
  • Berridge MJ. Inositol trisphosphate and calcium signalling. Nature. 1993 Jan 28;361(6410):315–325. [PubMed]
  • Berridge MJ, Irvine RF. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature. 1984 Nov 22;312(5992):315–321. [PubMed]
  • Bijsterbosch MK, Meade CJ, Turner GA, Klaus GG. B lymphocyte receptors and polyphosphoinositide degradation. Cell. 1985 Jul;41(3):999–1006. [PubMed]
  • Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573–584. [PubMed]
  • Brash DE, Reddel RR, Quanrud M, Yang K, Farrell MP, Harris CC. Strontium phosphate transfection of human cells in primary culture: stable expression of the simian virus 40 large-T-antigen gene in primary human bronchial epithelial cells. Mol Cell Biol. 1987 May;7(5):2031–2034. [PMC free article] [PubMed]
  • Brauweiler A, Garl P, Franklin AA, Giebler HA, Nyborg JK. A molecular mechanism for human T-cell leukemia virus latency and Tax transactivation. J Biol Chem. 1995 May 26;270(21):12814–12822. [PubMed]
  • Brooks PA, Nyborg JK, Cockerell GL. Identification of an NF-kappa B binding site in the bovine leukemia virus promoter. J Virol. 1995 Oct;69(10):6005–6009. [PMC free article] [PubMed]
  • Burny A, Bruck C, Cleuter Y, Couez D, Deschamps J, Gregoire D, Ghysdael J, Kettmann R, Mammerickx M, Marbaix G, et al. Bovine leukaemia virus and enzootic bovine leukosis. Onderstepoort J Vet Res. 1985 Sep;52(3):133–144. [PubMed]
  • Connor LM, Oxman MN, Brady JN, Marriott SJ. Twenty-one base pair repeat elements influence the ability of a Gal4-Tax fusion protein to transactivate the HTLV-I long terminal repeat. Virology. 1993 Aug;195(2):569–577. [PubMed]
  • Dash PK, Karl KA, Colicos MA, Prywes R, Kandel ER. cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):5061–5065. [PMC free article] [PubMed]
  • de Groot RP, Derua R, Goris J, Sassone-Corsi P. Phosphorylation and negative regulation of the transcriptional activator CREM by p34cdc2. Mol Endocrinol. 1993 Nov;7(11):1495–1450. [PubMed]
  • Derse D. Bovine leukemia virus transcription is controlled by a virus-encoded trans-acting factor and by cis-acting response elements. J Virol. 1987 Aug;61(8):2462–2471. [PMC free article] [PubMed]
  • Ellis MJ, Lindon AC, Flint KJ, Jones NC, Goodbourn S. Activating transcription factor-1 is a specific antagonist of the cyclic adenosine 3'.5'-monophosphate (cAMP) response element-binding protein-1-mediated response to cAMP. Mol Endocrinol. 1995 Feb;9(2):255–265. [PubMed]
  • Enslen H, Sun P, Brickey D, Soderling SH, Klamo E, Soderling TR. Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation. J Biol Chem. 1994 Jun 3;269(22):15520–15527. [PubMed]
  • Enslen H, Tokumitsu H, Soderling TR. Phosphorylation of CREB by CaM-kinase IV activated by CaM-kinase IV kinase. Biochem Biophys Res Commun. 1995 Feb 27;207(3):1038–1043. [PubMed]
  • Franklin AA, Kubik MF, Uittenbogaard MN, Brauweiler A, Utaisincharoen P, Matthews MA, Dynan WS, Hoeffler JP, Nyborg JK. Transactivation by the human T-cell leukemia virus Tax protein is mediated through enhanced binding of activating transcription factor-2 (ATF-2) ATF-2 response and cAMP element-binding protein (CREB). J Biol Chem. 1993 Oct 5;268(28):21225–21231. [PubMed]
  • Fujii M, Tsuchiya H, Seiki M. HTLV-1 Tax has distinct but overlapping domains for transcriptional activation and for enhancer specificity. Oncogene. 1991 Dec;6(12):2349–2352. [PubMed]
  • Fujisawa J, Toita M, Yoshimura T, Yoshida M. The indirect association of human T-cell leukemia virus tax protein with DNA results in transcriptional activation. J Virol. 1991 Aug;65(8):4525–4528. [PMC free article] [PubMed]
  • Ghysdael J, Bruck C, Kettmann R, Burny A. Bovine leukemia virus. Curr Top Microbiol Immunol. 1984;112:1–19. [PubMed]
  • Ginty DD, Bonni A, Greenberg ME. Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell. 1994 Jun 3;77(5):713–725. [PubMed]
  • Gonzalez GA, Menzel P, Leonard J, Fischer WH, Montminy MR. Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB. Mol Cell Biol. 1991 Mar;11(3):1306–1312. [PMC free article] [PubMed]
  • Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989 Nov 17;59(4):675–680. [PubMed]
  • Gonzalez GA, Yamamoto KK, Fischer WH, Karr D, Menzel P, Biggs W, 3rd, Vale WW, Montminy MR. A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989 Feb 23;337(6209):749–752. [PubMed]
  • Gupta P, Ferrer JF. Expression of bovine leukemia virus genome is blocked by a nonimmunoglobulin protein in plasma from infected cattle. Science. 1982 Jan 22;215(4531):405–407. [PubMed]
  • Hai TW, Liu F, Coukos WJ, Green MR. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989 Dec;3(12B):2083–2090. [PubMed]
  • Hanissian SH, Frangakis M, Bland MM, Jawahar S, Chatila TA. Expression of a Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, in human T lymphocytes. Regulation of kinase activity by T cell receptor signaling. J Biol Chem. 1993 Sep 25;268(27):20055–20063. [PubMed]
  • Hoeffler JP, Meyer TE, Yun Y, Jameson JL, Habener JF. Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science. 1988 Dec 9;242(4884):1430–1433. [PubMed]
  • Hurst HC, Masson N, Jones NC, Lee KA. 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. Mol Cell Biol. 1990 Dec;10(12):6192–6203. [PMC free article] [PubMed]
  • Hurst HC, Totty NF, Jones NC. Identification and functional characterisation of the cellular activating transcription factor 43 (ATF-43) protein. Nucleic Acids Res. 1991 Sep 11;19(17):4601–4609. [PMC free article] [PubMed]
  • Jefferson AB, Travis SM, Schulman H. Activation of multifunctional Ca2+/calmodulin-dependent protein kinase in GH3 cells. J Biol Chem. 1991 Jan 25;266(3):1484–1490. [PubMed]
  • Jensen WA, Wicks-Beard BJ, Cockerell GL. Inhibition of protein kinase C results in decreased expression of bovine leukemia virus. J Virol. 1992 Jul;66(7):4427–4433. [PMC free article] [PubMed]
  • Jones DA, Glod J, Wilson-Shaw D, Hahn WE, Sikela JM. cDNA sequence and differential expression of the mouse Ca2+/calmodulin-dependent protein kinase IV gene. FEBS Lett. 1991 Sep 2;289(1):105–109. [PubMed]
  • Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH. A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain. Mol Cell Biol. 1990 Apr;10(4):1347–1357. [PMC free article] [PubMed]
  • Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM. Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4820–4824. [PMC free article] [PubMed]
  • Katoh I, Yoshinaka Y, Ikawa Y. Bovine leukemia virus trans-activator p38tax activates heterologous promoters with a common sequence known as a cAMP-responsive element or the binding site of a cellular transcription factor ATF. EMBO J. 1989 Feb;8(2):497–503. [PMC free article] [PubMed]
  • Kettmann R, Cleuter Y, Mammerickx M, Meunier-Rotival M, Bernardi G, Burny A, Chantrenne H. Genomic integration of bovine leukemia provirus: comparison of persistent lymphocytosis with lymph node tumor form of enzootic. Proc Natl Acad Sci U S A. 1980 May;77(5):2577–2581. [PMC free article] [PubMed]
  • Kettmann R, Marbaix G, Cleuter Y, Portetelle D, Mammerickx M, Burny A. Genomic integration of bovine leukemia provirus and lack of viral RNA expression in the target cells of cattle with different responses to BLV infection. Leuk Res. 1980;4(6):509–519. [PubMed]
  • Kumar SP, Paul PS, Pomeroy KA, Johnson DW, Muscoplat CC, Van Der Maaten MJ, Miller JM, Sorensen DK. Frequency of lymphocytes bearing Fc receptors and surface membrane immunoglobulins in normal, persistent lymphocytotic and leukemia cows. Am J Vet Res. 1978 Jan;39(1):45–49. [PubMed]
  • Lagarias DM, Radke K. Transcriptional activation of bovine leukemia virus in blood cells from experimentally infected, asymptomatic sheep with latent infections. J Virol. 1989 May;63(5):2099–2107. [PMC free article] [PubMed]
  • Lee CQ, Yun YD, Hoeffler JP, Habener JF. Cyclic-AMP-responsive transcriptional activation of CREB-327 involves interdependent phosphorylated subdomains. EMBO J. 1990 Dec;9(13):4455–4465. [PMC free article] [PubMed]
  • Lin YS, Green MR. Interaction of a common cellular transcription factor, ATF, with regulatory elements in both E1a- and cyclic AMP-inducible promoters. Proc Natl Acad Sci U S A. 1988 May;85(10):3396–3400. [PMC free article] [PubMed]
  • Maekawa T, Sakura H, Kanei-Ishii C, Sudo T, Yoshimura T, Fujisawa J, Yoshida M, Ishii S. Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J. 1989 Jul;8(7):2023–2028. [PMC free article] [PubMed]
  • Matthews MA, Markowitz RB, Dynan WS. In vitro activation of transcription by the human T-cell leukemia virus type I Tax protein. Mol Cell Biol. 1992 May;12(5):1986–1996. [PMC free article] [PubMed]
  • Matthews RP, Guthrie CR, Wailes LM, Zhao X, Means AR, McKnight GS. Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol Cell Biol. 1994 Sep;14(9):6107–6116. [PMC free article] [PubMed]
  • Means AR, Cruzalegui F, LeMagueresse B, Needleman DS, Slaughter GR, Ono T. A novel Ca2+/calmodulin-dependent protein kinase and a male germ cell-specific calmodulin-binding protein are derived from the same gene. Mol Cell Biol. 1991 Aug;11(8):3960–3971. [PMC free article] [PubMed]
  • Miller JM, Miller LD, Olson C, Gillette KG. Virus-like particles in phytohemagglutinin-stimulated lymphocyte cultures with reference to bovine lymphosarcoma. J Natl Cancer Inst. 1969 Dec;43(6):1297–1305. [PubMed]
  • Montminy MR, Bilezikjian LM. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987 Jul 9;328(6126):175–178. [PubMed]
  • Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6682–6686. [PMC free article] [PubMed]
  • Mosialos G, Hanissian SH, Jawahar S, Vara L, Kieff E, Chatila TA. A Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, expressed after transformation of primary human B lymphocytes by Epstein-Barr virus (EBV) is induced by the EBV oncogene LMP1. J Virol. 1994 Mar;68(3):1697–1705. [PMC free article] [PubMed]
  • Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. [PubMed]
  • Ofir R, Dwarki VJ, Rashid D, Verma IM. Phosphorylation of the C terminus of Fos protein is required for transcriptional transrepression of the c-fos promoter. Nature. 1990 Nov 1;348(6296):80–82. [PubMed]
  • Onuma M, Honma T, Mikami T, Ichijo S, Konishi T. Studies on the sporadic and enzootic forms of bovine leukosis. J Comp Pathol. 1979 Apr;89(2):159–167. [PubMed]
  • Onuma M, Sagata N, Okada K, Ogawa Y, Ikawa Y, Oshima K. Integration of bovine leukemia virus DNA in the genomes of bovine lymphosarcoma cells. Microbiol Immunol. 1982;26(9):813–820. [PubMed]
  • Perini G, Wagner S, Green MR. Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax. Nature. 1995 Aug 17;376(6541):602–605. [PubMed]
  • Sheng M, McFadden G, Greenberg ME. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron. 1990 Apr;4(4):571–582. [PubMed]
  • Sheng M, Thompson MA, Greenberg ME. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427–1430. [PubMed]
  • Singh H, LeBowitz JH, Baldwin AS, Jr, Sharp PA. Molecular cloning of an enhancer binding protein: isolation by screening of an expression library with a recognition site DNA. Cell. 1988 Feb 12;52(3):415–423. [PubMed]
  • Srebrow A, Muro AF, Werbajh S, Sharp PA, Kornblihtt AR. The CRE-binding factor ATF-2 facilitates the occupation of the CCAAT box in the fibronectin gene promoter. FEBS Lett. 1993 Jul 19;327(1):25–28. [PubMed]
  • Stock ND, Ferrer JF. Replicating C-type virus in phytohemagglutinin-treated buffy-coat cultures of bovine origin. J Natl Cancer Inst. 1972 Apr;48(4):985–996. [PubMed]
  • Sun P, Enslen H, Myung PS, Maurer RA. Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev. 1994 Nov 1;8(21):2527–2539. [PubMed]
  • Suzuki T, Fujisawa JI, Toita M, Yoshida M. The trans-activator tax of human T-cell leukemia virus type 1 (HTLV-1) interacts with cAMP-responsive element (CRE) binding and CRE modulator proteins that bind to the 21-base-pair enhancer of HTLV-1. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):610–614. [PMC free article] [PubMed]
  • Thurmond MC, Holmberg CH, Picanso JP. Antibodies to bovine leukemia virus and presence of malignant lymphoma in slaughtered California dairy cattle. J Natl Cancer Inst. 1985 Mar;74(3):711–714. [PubMed]
  • Tratner I, Ofir R, Verma IM. Alteration of a cyclic AMP-dependent protein kinase phosphorylation site in the c-Fos protein augments its transforming potential. Mol Cell Biol. 1992 Mar;12(3):998–1006. [PMC free article] [PubMed]
  • Tsuchiya H, Fujii M, Tanaka Y, Tozawa H, Seiki M. Two distinct regions form a functional activation domain of the HTLV-1 trans-activator Tax1. Oncogene. 1994 Jan;9(1):337–340. [PubMed]
  • Van den Broeke A, Cleuter Y, Chen G, Portetelle D, Mammerickx M, Zagury D, Fouchard M, Coulombel L, Kettmann R, Burny A. Even transcriptionally competent proviruses are silent in bovine leukemia virus-induced sheep tumor cells. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9263–9267. [PMC free article] [PubMed]
  • Wagner S, Green MR. HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science. 1993 Oct 15;262(5132):395–399. [PubMed]
  • Weiland F, Straub OC. Differences in the in vitro response of lymphocytes from leukotic and normal cattle to concanavalin A. Res Vet Sci. 1976 May;20(3):340–341. [PubMed]
  • Willems L, Gegonne A, Chen G, Burny A, Kettmann R, Ghysdael J. The bovine leukemia virus p34 is a transactivator protein. EMBO J. 1987 Nov;6(11):3385–3389. [PMC free article] [PubMed]
  • Willems L, Kettmann R, Chen G, Portetelle D, Burny A, Derse D. Nucleotide sequence of the bovine cyclic-AMP responsive DNA binding protein (CREB2) cDNA. DNA Seq. 1991;1(6):415–417. [PubMed]
  • Willems L, Kettmann R, Chen G, Portetelle D, Burny A, Derse D. A cyclic AMP-responsive DNA-binding protein (CREB2) is a cellular transactivator of the bovine leukemia virus long terminal repeat. J Virol. 1992 Feb;66(2):766–772. [PMC free article] [PubMed]
  • Xie H, Rothstein TL. Protein kinase C mediates activation of nuclear cAMP response element-binding protein (CREB) in B lymphocytes stimulated through surface Ig. J Immunol. 1995 Feb 15;154(4):1717–1723. [PubMed]
  • Yamamoto KK, Gonzalez GA, Biggs WH, 3rd, Montminy MR. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. [PubMed]
  • Zandomeni RO, Carrera-Zandomeni M, Esteban E, Donawick W, Ferrer JF. Induction and inhibition of bovine leukaemia virus expression in naturally infected cells. J Gen Virol. 1992 Aug;73(Pt 8):1915–1924. [PubMed]
  • Zhao LJ, Giam CZ. Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7070–7074. [PMC free article] [PubMed]

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