Abstract
The human cytomegalovirus (HCMV) major immediate-early promoter (MIEP) is one of the first promoters to activate upon infection. To examine HCMV MIEP tissue-specific expression, transgenic mice were established containing the lacZ gene regulated by the MIEP (nucleotides -670 to +54). In the transgenic mice, lacZ expression was demonstrated in 19 of 29 tissues tested by histochemical and immunochemical analyses. These tissues included brain, eye, spinal cord, esophagus, stomach, pancreas, kidney, bladder, testis, ovary, spleen, salivary gland, thymus, bone marrow, skin, cartilage, and cardiac, striated and smooth muscles. Although expression was observed in multiple organs, promoter activity was restricted to specific cell types. The cell types which demonstrated HCMV MIEP expression included retinal cells of the eye, ductile cells of the salivary gland, exocrine cells of the pancreas, mucosal cells of the stomach and intestine, neuronal cells of the brain, muscle fibers, thecal cells of the corpus luteum, and Leydig and sperm cells of the testis. These observations indicate that the HCMV MIEP is not a pan-specific promoter and that the majority of expressing tissues correlate with tissues naturally infected by the virus in the human host.
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- Angulo A., Suto C., Boehm M. F., Heyman R. A., Ghazal P. Retinoid activation of retinoic acid receptors but not of retinoid X receptors promotes cellular differentiation and replication of human cytomegalovirus in embryonal cells. J Virol. 1995 Jun;69(6):3831–3837. doi: 10.1128/jvi.69.6.3831-3837.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baskar J. F., Smith P. P., Ciment G. S., Hoffmann S., Tucker C., Tenney D. J., Colberg-Poley A. M., Nelson J. A., Ghazal P. Developmental analysis of the cytomegalovirus enhancer in transgenic animals. J Virol. 1996 May;70(5):3215–3226. doi: 10.1128/jvi.70.5.3215-3226.1996. [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]
- Cameron J., Rigby R. J., van Deth A. G., Petrie J. J. Severe tubulo-interstitial disease in a renal allograft due to cytomegalovirus infection. Clin Nephrol. 1982 Dec;18(6):321–325. [PubMed] [Google Scholar]
- Chang Y. N., Crawford S., Stall J., Rawlins D. R., Jeang K. T., Hayward G. S. The palindromic series I repeats in the simian cytomegalovirus major immediate-early promoter behave as both strong basal enhancers and cyclic AMP response elements. J Virol. 1990 Jan;64(1):264–277. doi: 10.1128/jvi.64.1.264-277.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chee M. S., Bankier A. T., Beck S., Bohni R., Brown C. M., Cerny R., Horsnell T., Hutchison C. A., 3rd, Kouzarides T., Martignetti J. A. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol. 1990;154:125–169. doi: 10.1007/978-3-642-74980-3_6. [DOI] [PubMed] [Google Scholar]
- DeMarchi J. M., Schmidt C. A., Kaplan A. S. Patterns of transcription of human cytomegalovirus in permissively infected cells. J Virol. 1980 Aug;35(2):277–286. doi: 10.1128/jvi.35.2.277-286.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Diethelm A. G., Gore I., Ch'ien L. T., Sterling W. A., Morgan J. M. Gastrointestinal hemorrhage secondary to cytomegalovirus after renal transplantation. A case report and review of the problem. Am J Surg. 1976 Mar;131(3):371–374. doi: 10.1016/0002-9610(76)90136-7. [DOI] [PubMed] [Google Scholar]
- Farber S., Wolbach S. B. Intranuclear and Cytoplasmic Inclusions ("Protozoan-Like Bodies") in the Salivary Glands and Other Organs of Infants. Am J Pathol. 1932 Mar;8(2):123–136.3. [PMC free article] [PubMed] [Google Scholar]
- Furth P. A., Hennighausen L., Baker C., Beatty B., Woychick R. The variability in activity of the universally expressed human cytomegalovirus immediate early gene 1 enhancer/promoter in transgenic mice. Nucleic Acids Res. 1991 Nov 25;19(22):6205–6208. doi: 10.1093/nar/19.22.6205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ghazal P., DeMattei C., Giulietti E., Kliewer S. A., Umesono K., Evans R. M. Retinoic acid receptors initiate induction of the cytomegalovirus enhancer in embryonal cells. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7630–7634. doi: 10.1073/pnas.89.16.7630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ghazal P., Lubon H., Hennighausen L. Multiple sequence-specific transcription factors modulate cytomegalovirus enhancer activity in vitro. Mol Cell Biol. 1988 Apr;8(4):1809–1811. doi: 10.1128/mcb.8.4.1809. [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]
- Gnann J. W., Jr, Ahlmén J., Svalander C., Olding L., Oldstone M. B., Nelson J. A. Inflammatory cells in transplanted kidneys are infected by human cytomegalovirus. Am J Pathol. 1988 Aug;132(2):239–248. [PMC free article] [PubMed] [Google Scholar]
- HAYMAKER W., GIRDANY B. R., STEPHENS J., LILLIE R. D., FETTERMAN G. H. Cerebral involvement with advanced periventricular calcification in generalized cytomegalic inclusion disease in the newborn; a clinicopathological report of a case diagnosed during life. J Neuropathol Exp Neurol. 1954 Oct;13(4):562–586. doi: 10.1093/jnen/13.4.562. [DOI] [PubMed] [Google Scholar]
- Hunninghake G. W., Monick M. M., Liu B., Stinski M. F. The promoter-regulatory region of the major immediate-early gene of human cytomegalovirus responds to T-lymphocyte stimulation and contains functional cyclic AMP-response elements. J Virol. 1989 Jul;63(7):3026–3033. doi: 10.1128/jvi.63.7.3026-3033.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenson A. B., Rosenberg H. S., Notkins A. L. Pancreatic islet-cell damage in children with fatal viral infections. Lancet. 1980 Aug 16;2(8190):354–358. [PubMed] [Google Scholar]
- Kennedy P. G., Newsome D. A., Hess J., Narayan O., Suresch D. L., Green W. R., Gallo R. C., Polk B. F. Cytomegalovirus but not human T lymphotropic virus type III/lymphadenopathy associated virus detected by in situ hybridisation in retinal lesions in patients with the acquired immune deficiency syndrome. Br Med J (Clin Res Ed) 1986 Jul 19;293(6540):162–164. doi: 10.1136/bmj.293.6540.162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klemola E., Stenström R., von Essen R. Pneumonia as a clinical manifestation of cytomegalovirus infection in previously healthy adults. Scand J Infect Dis. 1972;4(1):7–10. doi: 10.3109/inf.1972.4.issue-1.02. [DOI] [PubMed] [Google Scholar]
- Koedood M., Fichtel A., Meier P., Mitchell P. J. Human cytomegalovirus (HCMV) immediate-early enhancer/promoter specificity during embryogenesis defines target tissues of congenital HCMV infection. J Virol. 1995 Apr;69(4):2194–2207. doi: 10.1128/jvi.69.4.2194-2207.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kondo K., Kaneshima H., Mocarski E. S. Human cytomegalovirus latent infection of granulocyte-macrophage progenitors. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11879–11883. doi: 10.1073/pnas.91.25.11879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kothari S., Baillie J., Sissons J. G., Sinclair J. H. The 21bp repeat element of the human cytomegalovirus major immediate early enhancer is a negative regulator of gene expression in undifferentiated cells. Nucleic Acids Res. 1991 Apr 25;19(8):1767–1771. doi: 10.1093/nar/19.8.1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LiVolsi V. A., Merino M. J. Cytomegalovirus infection of ovarian thecoma. Arch Pathol Lab Med. 1979 Nov;103(12):653–654. [PubMed] [Google Scholar]
- Liu B., Stinski M. F. Human cytomegalovirus contains a tegument protein that enhances transcription from promoters with upstream ATF and AP-1 cis-acting elements. J Virol. 1992 Jul;66(7):4434–4444. doi: 10.1128/jvi.66.7.4434-4444.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maciejewski J. P., Bruening E. E., Donahue R. E., Mocarski E. S., Young N. S., St Jeor S. C. Infection of hematopoietic progenitor cells by human cytomegalovirus. Blood. 1992 Jul 1;80(1):170–178. [PubMed] [Google Scholar]
- Melnick J. L., Adam E., Debakey M. E. Cytomegalovirus and atherosclerosis. Eur Heart J. 1993 Dec;14 (Suppl K):30–38. [PubMed] [Google Scholar]
- Morgello S., Cho E. S., Nielsen S., Devinsky O., Petito C. K. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome: an autopsy study of 30 cases and a review of the literature. Hum Pathol. 1987 Mar;18(3):289–297. doi: 10.1016/s0046-8177(87)80012-6. [DOI] [PubMed] [Google Scholar]
- Mueller N., Hinkula J., Wahren B. Elevated antibody titers against cytomegalovirus among patients with testicular cancer. Int J Cancer. 1988 Mar 15;41(3):399–403. doi: 10.1002/ijc.2910410314. [DOI] [PubMed] [Google Scholar]
- Nelson J. A., Gnann J. W., Jr, Ghazal P. Regulation and tissue-specific expression of human cytomegalovirus. Curr Top Microbiol Immunol. 1990;154:75–100. doi: 10.1007/978-3-642-74980-3_4. [DOI] [PubMed] [Google Scholar]
- Nelson J. A., Groudine M. Transcriptional regulation of the human cytomegalovirus major immediate-early gene is associated with induction of DNase I-hypersensitive sites. Mol Cell Biol. 1986 Feb;6(2):452–461. doi: 10.1128/mcb.6.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nelson J. A., Reynolds-Kohler C., Oldstone M. B., Wiley C. A. HIV and HCMV coinfect brain cells in patients with AIDS. Virology. 1988 Jul;165(1):286–290. doi: 10.1016/0042-6822(88)90685-x. [DOI] [PubMed] [Google Scholar]
- Nelson J. A., Reynolds-Kohler C., Smith B. A. Negative and positive regulation by a short segment in the 5'-flanking region of the human cytomegalovirus major immediate-early gene. Mol Cell Biol. 1987 Nov;7(11):4125–4129. doi: 10.1128/mcb.7.11.4125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nilaver G., Muldoon L. L., Kroll R. A., Pagel M. A., Breakefield X. O., Davidson B. L., Neuwelt E. A. Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9829–9833. doi: 10.1073/pnas.92.21.9829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Niller H. H., Hennighausen L. Phytohemagglutinin-induced activity of cyclic AMP (cAMP) response elements from cytomegalovirus is reduced by cyclosporine and synergistically enhanced by cAMP. J Virol. 1990 May;64(5):2388–2391. doi: 10.1128/jvi.64.5.2388-2391.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- ROQUE A. L., JAFAREY N. A., COULTER P. A STAIN FOR THE HISTOCHEMICAL DEMONSTRATION OF NUCLEIC ACIDS. Exp Mol Pathol. 1965 Jun;11:266–274. doi: 10.1016/0014-4800(65)90002-x. [DOI] [PubMed] [Google Scholar]
- Sambucetti L. C., Cherrington J. M., Wilkinson G. W., Mocarski E. S. NF-kappa B activation of the cytomegalovirus enhancer is mediated by a viral transactivator and by T cell stimulation. EMBO J. 1989 Dec 20;8(13):4251–4258. doi: 10.1002/j.1460-2075.1989.tb08610.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanes J. R., Rubenstein J. L., Nicolas J. F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 1986 Dec 1;5(12):3133–3142. doi: 10.1002/j.1460-2075.1986.tb04620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmidt E. V., Christoph G., Zeller R., Leder P. The cytomegalovirus enhancer: a pan-active control element in transgenic mice. Mol Cell Biol. 1990 Aug;10(8):4406–4411. doi: 10.1128/mcb.10.8.4406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shelbourn S. L., Kothari S. K., Sissons J. G., Sinclair J. H. Repression of human cytomegalovirus gene expression associated with a novel immediate early regulatory region binding factor. Nucleic Acids Res. 1989 Nov 25;17(22):9165–9171. doi: 10.1093/nar/17.22.9165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shorr R. I., Longo W. L., Oberley T. D., Bozdech M. J., Walker D. L. Cytomegalovirus-associated tubulointerstitial nephritis in an allogeneic bone marrow transplant recipient. Ann Intern Med. 1987 Sep;107(3):351–352. doi: 10.7326/0003-4819-107-2-351. [DOI] [PubMed] [Google Scholar]
- Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
- Speir E., Modali R., Huang E. S., Leon M. B., Shawl F., Finkel T., Epstein S. E. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science. 1994 Jul 15;265(5170):391–394. doi: 10.1126/science.8023160. [DOI] [PubMed] [Google Scholar]
- Stamminger T., Fickenscher H., Fleckenstein B. Cell type-specific induction of the major immediate early enhancer of human cytomegalovirus by cyclic AMP. J Gen Virol. 1990 Jan;71(Pt 1):105–113. doi: 10.1099/0022-1317-71-1-105. [DOI] [PubMed] [Google Scholar]
- Stenberg R. M., Depto A. S., Fortney J., Nelson J. A. Regulated expression of early and late RNAs and proteins from the human cytomegalovirus immediate-early gene region. J Virol. 1989 Jun;63(6):2699–2708. doi: 10.1128/jvi.63.6.2699-2708.1989. [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]
- Sterner G., Agell B. O., Wahren B., Espmark A. Acquired cytomegalovirus infection in older children and adults. A clinical study of hospitalized patients. Scand J Infect Dis. 1970;2(2):95–103. doi: 10.3109/inf.1970.2.issue-2.04. [DOI] [PubMed] [Google Scholar]
- Subietas A., Deppisch L. M., Astarloa J. Cytomegalovirus oophoritis: ovarian cortical necrosis. Hum Pathol. 1977 May;8(3):285–292. doi: 10.1016/s0046-8177(77)80025-7. [DOI] [PubMed] [Google Scholar]
- Teixidor H. S., Honig C. L., Norsoph E., Albert S., Mouradian J. A., Whalen J. P. Cytomegalovirus infection of the alimentary canal: radiologic findings with pathologic correlation. Radiology. 1987 May;163(2):317–323. doi: 10.1148/radiology.163.2.3031723. [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]
- WARD P. H., LINDSAY J. R., WARNER N. E. CYTOMEGALIC INCLUSION DISEASE AFFECTING THE TEMPORAL BONE. Laryngoscope. 1965 Apr;75:628–638. doi: 10.1288/00005537-196504000-00005. [DOI] [PubMed] [Google Scholar]
- Wathen M. W., Stinski M. F. Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate early, early, and late times after infection. J Virol. 1982 Feb;41(2):462–477. doi: 10.1128/jvi.41.2.462-477.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wiley C. A., Nelson J. A. Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Pathol. 1988 Oct;133(1):73–81. [PMC free article] [PubMed] [Google Scholar]
- Wiley C. A., Schrier R. D., Denaro F. J., Nelson J. A., Lampert P. W., Oldstone M. B. Localization of cytomegalovirus proteins and genome during fulminant central nervous system infection in an AIDS patient. J Neuropathol Exp Neurol. 1986 Mar;45(2):127–139. doi: 10.1097/00005072-198603000-00003. [DOI] [PubMed] [Google Scholar]