Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Nov;71(11):8176–8185. doi: 10.1128/jvi.71.11.8176-8185.1997

Identification of domains within the human cytomegalovirus major immediate-early 86-kilodalton protein and the retinoblastoma protein required for physical and functional interaction with each other.

E A Fortunato 1, M H Sommer 1, K Yoder 1, D H Spector 1
PMCID: PMC192274  PMID: 9343168

Abstract

The human cytomegalovirus major immediate-early 86-kDa protein (IE2 86) plays an important role in the trans activation and regulation of HCMV gene expression. Previously, we demonstrated that IE2 86 contains three regions (amino acids [aa] 86 to 135, 136 to 290, and 291 to 364) that can independently bind to in vitro-translated Rb when IE2 86 is produced as a glutathione S-transferase fusion protein (M. H. Sommer, A. L. Scully, and D. H. Spector, J. Virol. 68:6223-6231, 1994). In this report, we have elucidated the regions of Rb involved in binding to IE2 86 and have further analyzed the functional nature of the interaction between these two proteins. We find that two domains on Rb, the A/B pocket and the carboxy terminus, can each independently form a complex with IE2 86. In functional assays, we demonstrate that IE2 86 and another IE protein, IE1 72, can counter the enlarged flat cell phenotype, but not the G1/S block, which results from expression of wild-type Rb in the human osteosarcoma cell line Saos-2. Mutational analysis reveals that there are two domains on IE2 86 that can independently affect Rb function. One region (aa 241 to 369) includes the major Rb-binding domain, while the second maps to the amino-terminal region (aa 1 to 85) common to both IE2 86 and IE1 72. These data show that Rb and IE2 86 physically and functionally interact with each other via at least two separate domains and provide further support for the hypothesis that IE2 86 may exert its pleiotropic effects through the formation of multimeric protein complexes.

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albrecht T., Boldogh I., Fons M., Lee C. H., AbuBakar S., Russell J. M., Au W. W. Cell-activation responses to cytomegalovirus infection relationship to the phasing of CMV replication and to the induction of cellular damage. Subcell Biochem. 1989;15:157–202. [PubMed] [Google Scholar]
  2. Albrecht T., Fons M. P., Deng C. Z., Boldogh I. Increased frequency of specific locus mutation following human cytomegalovirus infection. Virology. 1997 Mar 31;230(1):48–61. doi: 10.1006/viro.1997.8467. [DOI] [PubMed] [Google Scholar]
  3. Arlt H., Lang D., Gebert S., Stamminger T. Identification of binding sites for the 86-kilodalton IE2 protein of human cytomegalovirus within an IE2-responsive viral early promoter. J Virol. 1994 Jul;68(7):4117–4125. doi: 10.1128/jvi.68.7.4117-4125.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bresnahan W. A., Boldogh I., Thompson E. A., Albrecht T. Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1. Virology. 1996 Oct 1;224(1):150–160. doi: 10.1006/viro.1996.0516. [DOI] [PubMed] [Google Scholar]
  5. Caswell R., Bryant L., Sinclair J. Human cytomegalovirus immediate-early 2 (IE2) protein can transactivate the human hsp70 promoter by alleviation of Dr1-mediated repression. J Virol. 1996 Jun;70(6):4028–4037. doi: 10.1128/jvi.70.6.4028-4037.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Caswell R., Hagemeier C., Chiou C. J., Hayward G., Kouzarides T., Sinclair J. The human cytomegalovirus 86K immediate early (IE) 2 protein requires the basic region of the TATA-box binding protein (TBP) for binding, and interacts with TBP and transcription factor TFIIB via regions of IE2 required for transcriptional regulation. J Gen Virol. 1993 Dec;74(Pt 12):2691–2698. doi: 10.1099/0022-1317-74-12-2691. [DOI] [PubMed] [Google Scholar]
  7. Chen P. L., Riley D. J., Chen-Kiang S., Lee W. H. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465–469. doi: 10.1073/pnas.93.1.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cherrington J. M., Khoury E. L., Mocarski E. S. Human cytomegalovirus ie2 negatively regulates alpha gene expression via a short target sequence near the transcription start site. J Virol. 1991 Feb;65(2):887–896. doi: 10.1128/jvi.65.2.887-896.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Choi K. S., Kim S. J., Kim S. The retinoblastoma gene product negatively regulates transcriptional activation mediated by the human cytomegalovirus IE2 protein. Virology. 1995 Apr 20;208(2):450–456. doi: 10.1006/viro.1995.1175. [DOI] [PubMed] [Google Scholar]
  10. Cress W. D., Nevins J. R. Use of the E2F transcription factor by DNA tumor virus regulatory proteins. Curr Top Microbiol Immunol. 1996;208:63–78. doi: 10.1007/978-3-642-79910-5_3. [DOI] [PubMed] [Google Scholar]
  11. DeGregori J., Kowalik T., Nevins J. R. Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes. Mol Cell Biol. 1995 Aug;15(8):4215–4224. doi: 10.1128/mcb.15.8.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dittmer D., Mocarski E. S. Human cytomegalovirus infection inhibits G1/S transition. J Virol. 1997 Feb;71(2):1629–1634. doi: 10.1128/jvi.71.2.1629-1634.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dunaief J. L., Strober B. E., Guha S., Khavari P. A., Alin K., Luban J., Begemann M., Crabtree G. R., Goff S. P. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell. 1994 Oct 7;79(1):119–130. doi: 10.1016/0092-8674(94)90405-7. [DOI] [PubMed] [Google Scholar]
  14. Furnari B. A., Poma E., Kowalik T. F., Huong S. M., Huang E. S. Human cytomegalovirus immediate-early gene 2 protein interacts with itself and with several novel cellular proteins. J Virol. 1993 Aug;67(8):4981–4991. doi: 10.1128/jvi.67.8.4981-4991.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gu W., Schneider J. W., Condorelli G., Kaushal S., Mahdavi V., Nadal-Ginard B. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell. 1993 Feb 12;72(3):309–324. doi: 10.1016/0092-8674(93)90110-c. [DOI] [PubMed] [Google Scholar]
  16. Hagemeier C., Bannister A. J., Cook A., Kouzarides T. The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1580–1584. doi: 10.1073/pnas.90.4.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hagemeier C., Caswell R., Hayhurst G., Sinclair J., Kouzarides T. Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J. 1994 Jun 15;13(12):2897–2903. doi: 10.1002/j.1460-2075.1994.tb06584.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hagemeier C., Walker S., Caswell R., Kouzarides T., Sinclair J. The human cytomegalovirus 80-kilodalton but not the 72-kilodalton immediate-early protein transactivates heterologous promoters in a TATA box-dependent mechanism and interacts directly with TFIID. J Virol. 1992 Jul;66(7):4452–4456. doi: 10.1128/jvi.66.7.4452-4456.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hateboer G., Timmers H. T., Rustgi A. K., Billaud M., van 't Veer L. J., Bernards R. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8489–8493. doi: 10.1073/pnas.90.18.8489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hayhurst G. P., Bryant L. A., Caswell R. C., Walker S. M., Sinclair J. H. CCAAT box-dependent activation of the TATA-less human DNA polymerase alpha promoter by the human cytomegalovirus 72-kilodalton major immediate-early protein. J Virol. 1995 Jan;69(1):182–188. doi: 10.1128/jvi.69.1.182-188.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hermiston T. W., Malone C. L., Stinski M. F. Human cytomegalovirus immediate-early two protein region involved in negative regulation of the major immediate-early promoter. J Virol. 1990 Jul;64(7):3532–3536. doi: 10.1128/jvi.64.7.3532-3536.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hiebert S. W. Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression. Mol Cell Biol. 1993 Jun;13(6):3384–3391. doi: 10.1128/mcb.13.6.3384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hinds P. W., Mittnacht S., Dulic V., Arnold A., Reed S. I., Weinberg R. A. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992 Sep 18;70(6):993–1006. doi: 10.1016/0092-8674(92)90249-c. [DOI] [PubMed] [Google Scholar]
  24. Huang H. J., Yee J. K., Shew J. Y., Chen P. L., Bookstein R., Friedmann T., Lee E. Y., Lee W. H. Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science. 1988 Dec 16;242(4885):1563–1566. doi: 10.1126/science.3201247. [DOI] [PubMed] [Google Scholar]
  25. Jault F. M., Jault J. M., Ruchti F., Fortunato E. A., Clark C., Corbeil J., Richman D. D., Spector D. H. Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest. J Virol. 1995 Nov;69(11):6697–6704. doi: 10.1128/jvi.69.11.6697-6704.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jenkins D. E., Martens C. L., Mocarski E. S. Human cytomegalovirus late protein encoded by ie2: a trans-activator as well as a repressor of gene expression. J Gen Virol. 1994 Sep;75(Pt 9):2337–2348. doi: 10.1099/0022-1317-75-9-2337. [DOI] [PubMed] [Google Scholar]
  27. Jupp R., Hoffmann S., Stenberg R. M., Nelson J. A., Ghazal P. Human cytomegalovirus IE86 protein interacts with promoter-bound TATA-binding protein via a specific region distinct from the autorepression domain. J Virol. 1993 Dec;67(12):7539–7546. doi: 10.1128/jvi.67.12.7539-7546.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kaye F. J., Kratzke R. A., Gerster J. L., Horowitz J. M. A single amino acid substitution results in a retinoblastoma protein defective in phosphorylation and oncoprotein binding. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6922–6926. doi: 10.1073/pnas.87.17.6922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Klucher K. M., Sommer M., Kadonaga J. T., Spector D. H. In vivo and in vitro analysis of transcriptional activation mediated by the human cytomegalovirus major immediate-early proteins. Mol Cell Biol. 1993 Feb;13(2):1238–1250. doi: 10.1128/mcb.13.2.1238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kwon H., Imbalzano A. N., Khavari P. A., Kingston R. E., Green M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature. 1994 Aug 11;370(6489):477–481. doi: 10.1038/370477a0. [DOI] [PubMed] [Google Scholar]
  31. Lang D., Gebert S., Arlt H., Stamminger T. Functional interaction between the human cytomegalovirus 86-kilodalton IE2 protein and the cellular transcription factor CREB. J Virol. 1995 Oct;69(10):6030–6037. doi: 10.1128/jvi.69.10.6030-6037.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lang D., Stamminger T. The 86-kilodalton IE-2 protein of human cytomegalovirus is a sequence-specific DNA-binding protein that interacts directly with the negative autoregulatory response element located near the cap site of the IE-1/2 enhancer-promoter. J Virol. 1993 Jan;67(1):323–331. doi: 10.1128/jvi.67.1.323-331.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Liu B., Hermiston T. W., Stinski M. F. A cis-acting element in the major immediate-early (IE) promoter of human cytomegalovirus is required for negative regulation by IE2. J Virol. 1991 Feb;65(2):897–903. doi: 10.1128/jvi.65.2.897-903.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lu M., Shenk T. Human cytomegalovirus infection inhibits cell cycle progression at multiple points, including the transition from G1 to S. J Virol. 1996 Dec;70(12):8850–8857. doi: 10.1128/jvi.70.12.8850-8857.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lukac D. M., Manuppello J. R., Alwine J. C. Transcriptional activation by the human cytomegalovirus immediate-early proteins: requirements for simple promoter structures and interactions with multiple components of the transcription complex. J Virol. 1994 Aug;68(8):5184–5193. doi: 10.1128/jvi.68.8.5184-5193.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Macias M. P., Stinski M. F. An in vitro system for human cytomegalovirus immediate early 2 protein (IE2)-mediated site-dependent repression of transcription and direct binding of IE2 to the major immediate early promoter. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):707–711. doi: 10.1073/pnas.90.2.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Margolis M. J., Pajovic S., Wong E. L., Wade M., Jupp R., Nelson J. A., Azizkhan J. C. Interaction of the 72-kilodalton human cytomegalovirus IE1 gene product with E2F1 coincides with E2F-dependent activation of dihydrofolate reductase transcription. J Virol. 1995 Dec;69(12):7759–7767. doi: 10.1128/jvi.69.12.7759-7767.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Morgenstern J. P., Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. doi: 10.1093/nar/18.12.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pizzorno M. C., Hayward G. S. The IE2 gene products of human cytomegalovirus specifically down-regulate expression from the major immediate-early promoter through a target sequence located near the cap site. J Virol. 1990 Dec;64(12):6154–6165. doi: 10.1128/jvi.64.12.6154-6165.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pizzorno M. C., Mullen M. A., Chang Y. N., Hayward G. S. The functionally active IE2 immediate-early regulatory protein of human cytomegalovirus is an 80-kilodalton polypeptide that contains two distinct activator domains and a duplicated nuclear localization signal. J Virol. 1991 Jul;65(7):3839–3852. doi: 10.1128/jvi.65.7.3839-3852.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Poma E. E., Kowalik T. F., Zhu L., Sinclair J. H., Huang E. S. The human cytomegalovirus IE1-72 protein interacts with the cellular p107 protein and relieves p107-mediated transcriptional repression of an E2F-responsive promoter. J Virol. 1996 Nov;70(11):7867–7877. doi: 10.1128/jvi.70.11.7867-7877.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Qian Y., Luckey C., Horton L., Esser M., Templeton D. J. Biological function of the retinoblastoma protein requires distinct domains for hyperphosphorylation and transcription factor binding. Mol Cell Biol. 1992 Dec;12(12):5363–5372. doi: 10.1128/mcb.12.12.5363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Qin X. Q., Chittenden T., Livingston D. M., Kaelin W. G., Jr Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 1992 Jun;6(6):953–964. doi: 10.1101/gad.6.6.953. [DOI] [PubMed] [Google Scholar]
  44. Qin X. Q., Livingston D. M., Ewen M., Sellers W. R., Arany Z., Kaelin W. G., Jr The transcription factor E2F-1 is a downstream target of RB action. Mol Cell Biol. 1995 Feb;15(2):742–755. doi: 10.1128/mcb.15.2.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Samaniego L. A., Tevethia M. J., Spector D. J. The human cytomegalovirus 86-kilodalton immediate-early 2 protein: synthesis as a precursor polypeptide and interaction with a 75-kilodalton protein of probable viral origin. J Virol. 1994 Feb;68(2):720–729. doi: 10.1128/jvi.68.2.720-729.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schwartz R., Helmich B., Spector D. H. CREB and CREB-binding proteins play an important role in the IE2 86-kilodalton protein-mediated transactivation of the human cytomegalovirus 2.2-kilobase RNA promoter. J Virol. 1996 Oct;70(10):6955–6966. doi: 10.1128/jvi.70.10.6955-6966.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schwartz R., Sommer M. H., Scully A., Spector D. H. Site-specific binding of the human cytomegalovirus IE2 86-kilodalton protein to an early gene promoter. J Virol. 1994 Sep;68(9):5613–5622. doi: 10.1128/jvi.68.9.5613-5622.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Scully A. L., Sommer M. H., Schwartz R., Spector D. H. The human cytomegalovirus IE2 86-kilodalton protein interacts with an early gene promoter via site-specific DNA binding and protein-protein associations. J Virol. 1995 Oct;69(10):6533–6540. doi: 10.1128/jvi.69.10.6533-6540.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sellers W. R., Rodgers J. W., Kaelin W. G., Jr A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11544–11548. doi: 10.1073/pnas.92.25.11544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shen Y., Zhu H., Shenk T. Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3341–3345. doi: 10.1073/pnas.94.7.3341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Shew J. Y., Lin B. T., Chen P. L., Tseng B. Y., Yang-Feng T. L., Lee W. H. C-terminal truncation of the retinoblastoma gene product leads to functional inactivation. Proc Natl Acad Sci U S A. 1990 Jan;87(1):6–10. doi: 10.1073/pnas.87.1.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sommer M. H., Scully A. L., Spector D. H. Transactivation by the human cytomegalovirus IE2 86-kilodalton protein requires a domain that binds to both the TATA box-binding protein and the retinoblastoma protein. J Virol. 1994 Oct;68(10):6223–6231. doi: 10.1128/jvi.68.10.6223-6231.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Spector D. J., Tevethia M. J. Protein-protein interactions between human cytomegalovirus IE2-580aa and pUL84 in lytically infected cells. J Virol. 1994 Nov;68(11):7549–7553. doi: 10.1128/jvi.68.11.7549-7553.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. 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]
  55. Strober B. E., Dunaief J. L., Guha, Goff S. P. Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins. Mol Cell Biol. 1996 Apr;16(4):1576–1583. doi: 10.1128/mcb.16.4.1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Taya Y. RB kinases and RB-binding proteins: new points of view. Trends Biochem Sci. 1997 Jan;22(1):14–17. doi: 10.1016/s0968-0004(96)10070-0. [DOI] [PubMed] [Google Scholar]
  57. Templeton D. J., Park S. H., Lanier L., Weinberg R. A. Nonfunctional mutants of the retinoblastoma protein are characterized by defects in phosphorylation, viral oncoprotein association, and nuclear tethering. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3033–3037. doi: 10.1073/pnas.88.8.3033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Tsai H. L., Kou G. H., Chen S. C., Wu C. W., Lin Y. S. Human cytomegalovirus immediate-early protein IE2 tethers a transcriptional repression domain to p53. J Biol Chem. 1996 Feb 16;271(7):3534–3540. [PubMed] [Google Scholar]
  59. Wang J. Y., Knudsen E. S., Welch P. J. The retinoblastoma tumor suppressor protein. Adv Cancer Res. 1994;64:25–85. doi: 10.1016/s0065-230x(08)60834-9. [DOI] [PubMed] [Google Scholar]
  60. Wang J. Y. Retinoblastoma protein in growth suppression and death protection. Curr Opin Genet Dev. 1997 Feb;7(1):39–45. doi: 10.1016/s0959-437x(97)80107-4. [DOI] [PubMed] [Google Scholar]
  61. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  62. Welch P. J., Wang J. Y. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell. 1993 Nov 19;75(4):779–790. doi: 10.1016/0092-8674(93)90497-e. [DOI] [PubMed] [Google Scholar]
  63. Welch P. J., Wang J. Y. Abrogation of retinoblastoma protein function by c-Abl through tyrosine kinase-dependent and -independent mechanisms. Mol Cell Biol. 1995 Oct;15(10):5542–5551. doi: 10.1128/mcb.15.10.5542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Welch P. J., Wang J. Y. Disruption of retinoblastoma protein function by coexpression of its C pocket fragment. Genes Dev. 1995 Jan 1;9(1):31–46. doi: 10.1101/gad.9.1.31. [DOI] [PubMed] [Google Scholar]
  65. Yoo Y. D., Chiou C. J., Choi K. S., Yi Y., Michelson S., Kim S., Hayward G. S., Kim S. J. The IE2 regulatory protein of human cytomegalovirus induces expression of the human transforming growth factor beta1 gene through an Egr-1 binding site. J Virol. 1996 Oct;70(10):7062–7070. doi: 10.1128/jvi.70.10.7062-7070.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zhou Y. F., Leon M. B., Waclawiw M. A., Popma J. J., Yu Z. X., Finkel T., Epstein S. E. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med. 1996 Aug 29;335(9):624–630. doi: 10.1056/NEJM199608293350903. [DOI] [PubMed] [Google Scholar]
  67. Zhu H., Shen Y., Shenk T. Human cytomegalovirus IE1 and IE2 proteins block apoptosis. J Virol. 1995 Dec;69(12):7960–7970. doi: 10.1128/jvi.69.12.7960-7970.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES