Functional Interaction Between the HCMV IE2 Transactivator and the Retinoblastoma Protein

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1994 Jun 15

PMID 8026474

Citations 92

Authors

C Hagemeier

R Caswell

G Hayhurst

J Sinclair

T Kouzarides

Affiliations

Soon will be listed here.

Abstract

The 86 kDa immediate early IE2 protein of human cytomegalovirus (HCMV) can activate transcription of both viral and cellular genes and can repress transcription from its own promoter. Using two in vivo assays, we provide evidence of a functional interaction between IE2 and the retinoblastoma (RB) protein: IE2 alleviates RB-induced repression of a promoter bearing E2F binding sites and RB alleviates IE2-mediated repression of its own promoter. These functional effects are likely to be a result of a direct contact between IE2 and RB, which we can demonstrate both in vitro and in HCMV-infected cells. The interaction between IE2 and RB shows similar characteristics to the interaction between RB and E1A. First, binding to IE2 requires an intact RB pocket domain. Secondly, the binding is sensitive to the phosphorylation state of RB, because cyclin A-CDK-induced phosphorylation of RB diminishes IE2 binding. Thirdly, the IE2 domain required for RB binding is separate to the domains necessary for TBP and TFIIB binding. Our results demonstrate that large and small DNA viruses have a common interface with the host cell, namely the association with the RB tumour suppressor protein.

Citing Articles

HPV and HCMV in Cervical Cancer: A Review of Their Co-Occurrence in Premalignant and Malignant Lesions.

Blanco R, Munoz J Viruses. 2024; 16(11).

PMID: 39599814 PMC: 11599080. DOI: 10.3390/v16111699.

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus.

Wu X, Zhou X, Wang S, Mao G Virol J. 2023; 20(1):250.

PMID: 37915066 PMC: 10621139. DOI: 10.1186/s12985-023-02203-y.

The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme.

Daei Sorkhabi A, Sarkesh A, Saeedi H, Marofi F, Ghaebi M, Silvestris N Front Oncol. 2022; 12:818447.

PMID: 35515137 PMC: 9062077. DOI: 10.3389/fonc.2022.818447.

Emerging Mechanisms of G/S Cell Cycle Control by Human and Mouse Cytomegaloviruses.

Bogdanow B, Phan Q, Wiebusch L mBio. 2021; 12(6):e0293421.

PMID: 34903047 PMC: 8669474. DOI: 10.1128/mBio.02934-21.

Valganciclovir as Add-On to Standard Therapy in Secondary Glioblastoma.

Stragliotto G, Pantalone M, Rahbar A, Soderberg-Naucler C Microorganisms. 2020; 8(10).

PMID: 32987955 PMC: 7599902. DOI: 10.3390/microorganisms8101471.

References

St Jeor S, Hutt R . Cell DNA replication as a function in the synthesis of human cytomegalovirus. J Gen Virol. 1977; 37(1):65-73. DOI: 10.1099/0022-1317-37-1-65. View

Rustgi A, Dyson N, Bernards R . Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product. Nature. 1991; 352(6335):541-4. DOI: 10.1038/352541a0. View

Malone C, Vesole D, Stinski M . Transactivation of a human cytomegalovirus early promoter by gene products from the immediate-early gene IE2 and augmentation by IE1: mutational analysis of the viral proteins. J Virol. 1990; 64(4):1498-506. PMC: 249283. DOI: 10.1128/JVI.64.4.1498-1506.1990. View

Caswell R, Hagemeier C, Chiou C, 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; 74 ( Pt 12):2691-8. DOI: 10.1099/0022-1317-74-12-2691. View

Helin K, Lees J, Vidal M, Dyson N, Harlow E, Fattaey A . A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell. 1992; 70(2):337-50. DOI: 10.1016/0092-8674(92)90107-n. View

Hollingsworth Jr R, Hensey C, Lee W . Retinoblastoma protein and the cell cycle. Curr Opin Genet Dev. 1993; 3(1):55-62. DOI: 10.1016/s0959-437x(05)80341-7. View

Kouzarides T . Transcriptional regulation by the retinoblastoma protein. Trends Cell Biol. 1993; 3(7):211-3. DOI: 10.1016/0962-8924(93)90113-f. View

Shan B, Zhu X, Chen P, Durfee T, Yang Y, Sharp D . Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F. Mol Cell Biol. 1992; 12(12):5620-31. PMC: 360501. DOI: 10.1128/mcb.12.12.5620-5631.1992. View

Wade M, Kowalik T, Mudryj M, Huang E, Azizkhan J . E2F mediates dihydrofolate reductase promoter activation and multiprotein complex formation in human cytomegalovirus infection. Mol Cell Biol. 1992; 12(10):4364-74. PMC: 360360. DOI: 10.1128/mcb.12.10.4364-4374.1992. View

10.

Weinberg R . Tumor suppressor genes. Science. 1991; 254(5035):1138-46. DOI: 10.1126/science.1659741. View

11.

Spector D, Tevethia M . Identification of a human cytomegalovirus virus DNA segment that complements an adenovirus 5 immediate early mutant. Virology. 1986; 151(2):329-38. DOI: 10.1016/0042-6822(86)90053-x. View

12.

Dalton S . Cell cycle regulation of the human cdc2 gene. EMBO J. 1992; 11(5):1797-804. PMC: 556637. DOI: 10.1002/j.1460-2075.1992.tb05231.x. View

13.

Hagemeier C, Bannister A, 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; 90(4):1580-4. PMC: 45918. DOI: 10.1073/pnas.90.4.1580. View

14.

Gu W, Schneider J, 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; 72(3):309-24. DOI: 10.1016/0092-8674(93)90110-c. View

15.

Pizzorno M, OHare P, Sha L, LaFemina R, Hayward G . trans-activation and autoregulation of gene expression by the immediate-early region 2 gene products of human cytomegalovirus. J Virol. 1988; 62(4):1167-79. PMC: 253124. DOI: 10.1128/JVI.62.4.1167-1179.1988. View

16.

Helin K, Ed H . The retinoblastoma protein as a transcriptional repressor. Trends Cell Biol. 1993; 3(2):43-6. DOI: 10.1016/0962-8924(93)90150-y. View

17.

Wang C, Petryniak B, Thompson C, Kaelin W, Leiden J . Regulation of the Ets-related transcription factor Elf-1 by binding to the retinoblastoma protein. Science. 1993; 260(5112):1330-5. DOI: 10.1126/science.8493578. View

18.

Wathen M, Stinski M . Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate early, early, and late times after infection. J Virol. 1982; 41(2):462-77. PMC: 256775. DOI: 10.1128/JVI.41.2.462-477.1982. View

19.

Kaelin Jr W, Krek W, Sellers W, DeCaprio J, Ajchenbaum F, Fuchs C . Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992; 70(2):351-64. DOI: 10.1016/0092-8674(92)90108-o. View

20.

Chellappan S, Hiebert S, Mudryj M, Horowitz J, Nevins J . The E2F transcription factor is a cellular target for the RB protein. Cell. 1991; 65(6):1053-61. DOI: 10.1016/0092-8674(91)90557-f. View