Abstract
The expression of alpha (immediate-early) genes of cytomegalovirus is regulated via a complex enhancer that consists of several different repeat elements. We describe here the autoinduction of expression from the alpha promoter-enhancer by the most abundant alpha gene product, a 491-amino-acid nuclear phosphoprotein referred to as ie1. We defined the 18-base-pair repeat element within the alpha enhancer as the signal through which ie1 acts to regulate gene expression. This element contains an NF kappa B site that may play an important role in ie1 autoregulation. Our analysis, which relied on deletions through the enhancer as well as reconstitution of responsiveness to a promoter with synthetic 18-base-pair repeats, strongly implicated ie1 in the transcriptional transactivation of the alpha promoter through its enhancer.
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Selected References
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- Akrigg A., Wilkinson G. W., Oram J. D. The structure of the major immediate early gene of human cytomegalovirus strain AD169. Virus Res. 1985 Mar;2(2):107–121. doi: 10.1016/0168-1702(85)90242-4. [DOI] [PubMed] [Google Scholar]
- Batterson W., Roizman B. Characterization of the herpes simplex virion-associated factor responsible for the induction of alpha genes. J Virol. 1983 May;46(2):371–377. doi: 10.1128/jvi.46.2.371-377.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boshart M., Weber F., Jahn G., Dorsch-Häsler K., Fleckenstein B., Schaffner W. A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell. 1985 Jun;41(2):521–530. doi: 10.1016/s0092-8674(85)80025-8. [DOI] [PubMed] [Google Scholar]
- Campbell M. E., Palfreyman J. W., Preston C. M. Identification of herpes simplex virus DNA sequences which encode a trans-acting polypeptide responsible for stimulation of immediate early transcription. J Mol Biol. 1984 Nov 25;180(1):1–19. doi: 10.1016/0022-2836(84)90427-3. [DOI] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Dorsch-Häsler K., Keil G. M., Weber F., Jasin M., Schaffner W., Koszinowski U. H. A long and complex enhancer activates transcription of the gene coding for the highly abundant immediate early mRNA in murine cytomegalovirus. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8325–8329. doi: 10.1073/pnas.82.24.8325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geballe A. P., Leach F. S., Mocarski E. S. Regulation of cytomegalovirus late gene expression: gamma genes are controlled by posttranscriptional events. J Virol. 1986 Mar;57(3):864–874. doi: 10.1128/jvi.57.3.864-874.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geballe A. P., Spaete R. R., Mocarski E. S. A cis-acting element within the 5' leader of a cytomegalovirus beta transcript determines kinetic class. Cell. 1986 Sep 12;46(6):865–872. doi: 10.1016/0092-8674(86)90068-1. [DOI] [PubMed] [Google Scholar]
- Ghazal P., Lubon H., Fleckenstein B., Hennighausen L. Binding of transcription factors and creation of a large nucleoprotein complex on the human cytomegalovirus enhancer. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3658–3662. doi: 10.1073/pnas.84.11.3658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ghazal P., Lubon H., Hennighausen L. Specific interactions between transcription factors and the promoter-regulatory region of the human cytomegalovirus major immediate-early gene. J Virol. 1988 Mar;62(3):1076–1079. doi: 10.1128/jvi.62.3.1076-1079.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gibson W. Protein counterparts of human and simian cytomegaloviruses. Virology. 1983 Jul 30;128(2):391–406. doi: 10.1016/0042-6822(83)90265-9. [DOI] [PubMed] [Google Scholar]
- Hennighausen L., Fleckenstein B. Nuclear factor 1 interacts with five DNA elements in the promoter region of the human cytomegalovirus major immediate early gene. EMBO J. 1986 Jun;5(6):1367–1371. doi: 10.1002/j.1460-2075.1986.tb04368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hermiston T. W., Malone C. L., Witte P. R., Stinski M. F. Identification and characterization of the human cytomegalovirus immediate-early region 2 gene that stimulates gene expression from an inducible promoter. J Virol. 1987 Oct;61(10):3214–3221. doi: 10.1128/jvi.61.10.3214-3221.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jeang K. T., Rawlins D. R., Rosenfeld P. J., Shero J. H., Kelly T. J., Hayward G. S. Multiple tandemly repeated binding sites for cellular nuclear factor 1 that surround the major immediate-early promoters of simian and human cytomegalovirus. J Virol. 1987 May;61(5):1559–1570. doi: 10.1128/jvi.61.5.1559-1570.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988 Mar;2(3):267–281. doi: 10.1101/gad.2.3.267. [DOI] [PubMed] [Google Scholar]
- Keil G. M., Ebeling-Keil A., Koszinowski U. H. Sequence and structural organization of murine cytomegalovirus immediate-early gene 1. J Virol. 1987 Jun;61(6):1901–1908. doi: 10.1128/jvi.61.6.1901-1908.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koszinowski U. H., Keil G. M., Volkmer H., Fibi M. R., Ebeling-Keil A., Münch K. The 89,000-Mr murine cytomegalovirus immediate-early protein activates gene transcription. J Virol. 1986 Apr;58(1):59–66. doi: 10.1128/jvi.58.1.59-66.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kouzarides T., Bankier A. T., Satchwell S. C., Preddy E., Barrell B. G. An immediate early gene of human cytomegalovirus encodes a potential membrane glycoprotein. Virology. 1988 Jul;165(1):151–164. doi: 10.1016/0042-6822(88)90668-x. [DOI] [PubMed] [Google Scholar]
- Michelson-Fiske S., Horodniceanu F., Guillon J. C. Immediate early antigens in human cytomegalovirus infected cells. Nature. 1977 Dec 15;270(5638):615–617. doi: 10.1038/270615a0. [DOI] [PubMed] [Google Scholar]
- Mocarski E. S., Stinski M. F. Persistence of the cytomegalovirus genome in human cells. J Virol. 1979 Sep;31(3):761–775. doi: 10.1128/jvi.31.3.761-775.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montminy M. R., Sevarino K. A., Wagner J. A., Mandel G., Goodman R. H. 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. doi: 10.1073/pnas.83.18.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
- Pellett P. E., McKnight J. L., Jenkins F. J., Roizman B. Nucleotide sequence and predicted amino acid sequence of a protein encoded in a small herpes simplex virus DNA fragment capable of trans-inducing alpha genes. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5870–5874. doi: 10.1073/pnas.82.17.5870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pizzorno M. C., O'Hare P., Sha L., LaFemina R. L., Hayward G. S. trans-activation and autoregulation of gene expression by the immediate-early region 2 gene products of human cytomegalovirus. J Virol. 1988 Apr;62(4):1167–1179. doi: 10.1128/jvi.62.4.1167-1179.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Post L. E., Mackem S., Roizman B. Regulation of alpha genes of herpes simplex virus: expression of chimeric genes produced by fusion of thymidine kinase with alpha gene promoters. Cell. 1981 May;24(2):555–565. doi: 10.1016/0092-8674(81)90346-9. [DOI] [PubMed] [Google Scholar]
- Rice G. P., Schrier R. D., Oldstone M. B. Cytomegalovirus infects human lymphocytes and monocytes: virus expression is restricted to immediate-early gene products. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6134–6138. doi: 10.1073/pnas.81.19.6134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schrier R. D., Nelson J. A., Oldstone M. B. Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection. Science. 1985 Nov 29;230(4729):1048–1051. doi: 10.1126/science.2997930. [DOI] [PubMed] [Google Scholar]
- Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. doi: 10.1016/0092-8674(86)90346-6. [DOI] [PubMed] [Google Scholar]
- Spaete R. R., Mocarski E. S. Regulation of cytomegalovirus gene expression: alpha and beta promoters are trans activated by viral functions in permissive human fibroblasts. J Virol. 1985 Oct;56(1):135–143. doi: 10.1128/jvi.56.1.135-143.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stenberg R. M., Stinski M. F. Autoregulation of the human cytomegalovirus major immediate-early gene. J Virol. 1985 Dec;56(3):676–682. doi: 10.1128/jvi.56.3.676-682.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stenberg R. M., Thomsen D. R., Stinski M. F. Structural analysis of the major immediate early gene of human cytomegalovirus. J Virol. 1984 Jan;49(1):190–199. doi: 10.1128/jvi.49.1.190-199.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stenberg R. M., Witte P. R., Stinski M. F. Multiple spliced and unspliced transcripts from human cytomegalovirus immediate-early region 2 and evidence for a common initiation site within immediate-early region 1. J Virol. 1985 Dec;56(3):665–675. doi: 10.1128/jvi.56.3.665-675.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stinski M. F., Roehr T. J. Activation of the major immediate early gene of human cytomegalovirus by cis-acting elements in the promoter-regulatory sequence and by virus-specific trans-acting components. J Virol. 1985 Aug;55(2):431–441. doi: 10.1128/jvi.55.2.431-441.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stinski M. F., Thomsen D. R., Stenberg R. M., Goldstein L. C. Organization and expression of the immediate early genes of human cytomegalovirus. J Virol. 1983 Apr;46(1):1–14. doi: 10.1128/jvi.46.1.1-14.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tanaka S., Otsuka M., Ihara S., Maeda F., Watanabe Y. Induction of pre-early nuclear antigen(s) in HEL cells infected with human cytomegalovirus. Microbiol Immunol. 1979;23(4):263–271. doi: 10.1111/j.1348-0421.1979.tb00462.x. [DOI] [PubMed] [Google Scholar]
- Thomsen D. R., Stenberg R. M., Goins W. F., Stinski M. F. Promoter-regulatory region of the major immediate early gene of human cytomegalovirus. Proc Natl Acad Sci U S A. 1984 Feb;81(3):659–663. doi: 10.1073/pnas.81.3.659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomsen D. R., Stinski M. F. Cloning of the human cytomegalovirus genome as endonuclease XbaI fragments. Gene. 1981 Dec;16(1-3):207–216. doi: 10.1016/0378-1119(81)90077-9. [DOI] [PubMed] [Google Scholar]
- Weston K. An enhancer element in the short unique region of human cytomegalovirus regulates the production of a group of abundant immediate early transcripts. Virology. 1988 Feb;162(2):406–416. doi: 10.1016/0042-6822(88)90481-3. [DOI] [PubMed] [Google Scholar]
- Wilkinson G. W., Akrigg A., Greenaway P. J. Transcription of the immediate early genes of human cytomegalovirus strain AD169. Virus Res. 1984;1(2):101–106. doi: 10.1016/0168-1702(84)90067-4. [DOI] [PubMed] [Google Scholar]