The Papillomavirus E2 Protein Binds to and Synergizes with C/EBP Factors Involved in Keratinocyte Differentiation

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2003 Apr 15

PMID 12692227

Citations 36

Authors

Dirk Hadaschik

Korinna Hinterkeuser

Monika Oldak

Herbert J Pfister

Sigrun Smola-Hess

Affiliations

Soon will be listed here.

Abstract

The papillomavirus life cycle is closely linked to the differentiation program of the host keratinocyte. Thus, late gene expression and viral maturation are restricted to terminally differentiated keratinocytes. A variety of cellular transcription factors including those of the C/EBP family are involved in the regulation of keratinocyte differentiation. In this study we show that the papillomavirus transcription factor E2 cooperates with C/EBPalpha and -beta in transcriptional activation. This synergism was independent of an E2 binding site. E2 and C/EBP factors synergistically transactivated a synthetic promoter construct containing classical C/EBPbeta sites and the C/EBPalpha-responsive proximal promoter of the involucrin gene, which is naturally expressed in differentiating keratinocytes. C/EBPalpha or -beta coprecipitated with E2 proteins derived from human papillomavirus type 8 (HPV8), HPV16, HPV18, and bovine papillomavirus type 1 in vitro and in vivo, indicating complex formation by the cellular and viral factors. The interaction domains could be mapped to the C terminus of E2 and amino acids 261 to 302 located within the bZIP motif of C/EBPbeta. Our data suggest that E2, via its interaction with C/EBP factors, may contribute to enhancing keratinocyte differentiation, which is suppressed by the viral oncoproteins E6 and E7 in HPV-induced lesions.

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References

Yao J, Breiding D, Androphy E . Functional interaction of the bovine papillomavirus E2 transactivation domain with TFIIB. J Virol. 1998; 72(2):1013-9. PMC: 124572. DOI: 10.1128/JVI.72.2.1013-1019.1998. View

Stevenson M, Hudson L, Burns J, Stewart R, Wells M, Maitland N . Inverse relationship between the expression of the human papillomavirus type 16 transcription factor E2 and virus DNA copy number during the progression of cervical intraepithelial neoplasia. J Gen Virol. 2000; 81(Pt 7):1825-32. DOI: 10.1099/0022-1317-81-7-1825. View

Lee K, Broker T, Chow L . Transcription factor YY1 represses cell-free replication from human papillomavirus origins. J Virol. 1998; 72(6):4911-7. PMC: 110050. DOI: 10.1128/JVI.72.6.4911-4917.1998. View

Oh H, Smart R . Expression of CCAAT/enhancer binding proteins (C/EBP) is associated with squamous differentiation in epidermis and isolated primary keratinocytes and is altered in skin neoplasms. J Invest Dermatol. 1998; 110(6):939-45. DOI: 10.1046/j.1523-1747.1998.00199.x. View

Heike T, Miyatake S, Yoshida M, Arai K, Arai N . Bovine papilloma virus encoded E2 protein activates lymphokine genes through DNA elements, distinct from the consensus motif, in the long control region of its own genome. EMBO J. 1989; 8(5):1411-7. PMC: 400968. DOI: 10.1002/j.1460-2075.1989.tb03522.x. View

Schreiber E, Matthias P, Muller M, Schaffner W . Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989; 17(15):6419. PMC: 318318. DOI: 10.1093/nar/17.15.6419. View

Akira S, Isshiki H, Sugita T, TANABE O, Kinoshita S, Nishio Y . A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990; 9(6):1897-906. PMC: 551896. DOI: 10.1002/j.1460-2075.1990.tb08316.x. View

Li R, Knight J, Jackson S, Tjian R, Botchan M . Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription. Cell. 1991; 65(3):493-505. DOI: 10.1016/0092-8674(91)90467-d. View

Scheffner M, Munger K, Byrne J, Howley P . The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991; 88(13):5523-7. PMC: 51909. DOI: 10.1073/pnas.88.13.5523. View

10.

Wells S, Francis D, Karpova A, Dowhanick J, Benson J, Howley P . Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways. EMBO J. 2000; 19(21):5762-71. PMC: 305788. DOI: 10.1093/emboj/19.21.5762. View

11.

Erickson R, Hemati N, Ross S, MacDougald O . p300 coactivates the adipogenic transcription factor CCAAT/enhancer-binding protein alpha. J Biol Chem. 2001; 276(19):16348-55. DOI: 10.1074/jbc.m100128200. View

12.

Smola-Hess S, de Silva U, Hadaschik D, Pfister H . Soluble interleukin-6 receptor activates the human papillomavirus type 18 long control region in SW756 cervical carcinoma cells in a STAT3-dependent manner. J Gen Virol. 2001; 82(Pt 10):2335-2339. DOI: 10.1099/0022-1317-82-10-2335. View

13.

Steger G, Schnabel C, Schmidt H . The hinge region of the human papillomavirus type 8 E2 protein activates the human p21(WAF1/CIP1) promoter via interaction with Sp1. J Gen Virol. 2002; 83(Pt 3):503-510. DOI: 10.1099/0022-1317-83-3-503. View

14.

Ramji D, Foka P . CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002; 365(Pt 3):561-75. PMC: 1222736. DOI: 10.1042/BJ20020508. View

15.

Muller A, Ritzkowsky A, Steger G . Cooperative activation of human papillomavirus type 8 gene expression by the E2 protein and the cellular coactivator p300. J Virol. 2002; 76(21):11042-53. PMC: 136630. DOI: 10.1128/jvi.76.21.11042-11053.2002. View

16.

Schlegel R, Phelps W, Zhang Y, Barbosa M . Quantitative keratinocyte assay detects two biological activities of human papillomavirus DNA and identifies viral types associated with cervical carcinoma. EMBO J. 1988; 7(10):3181-7. PMC: 454709. DOI: 10.1002/j.1460-2075.1988.tb03185.x. View

17.

Haugen T, Turek L, Mercurio F, Cripe T, Olson B, Anderson R . Sequence-specific and general transcriptional activation by the bovine papillomavirus-1 E2 trans-activator require an N-terminal amphipathic helix-containing E2 domain. EMBO J. 1988; 7(13):4245-53. PMC: 455138. DOI: 10.1002/j.1460-2075.1988.tb03322.x. View

18.

Hoffmann A, Roeder R . Purification of his-tagged proteins in non-denaturing conditions suggests a convenient method for protein interaction studies. Nucleic Acids Res. 1991; 19(22):6337-8. PMC: 329157. DOI: 10.1093/nar/19.22.6337. View

19.

Woodworth C, Cheng S, Simpson S, Hamacher L, Chow L, Broker T . Recombinant retroviruses encoding human papillomavirus type 18 E6 and E7 genes stimulate proliferation and delay differentiation of human keratinocytes early after infection. Oncogene. 1992; 7(4):619-26. View

20.

Hwang E, Riese 2nd D, Settleman J, Nilson L, Honig J, Flynn S . Inhibition of cervical carcinoma cell line proliferation by the introduction of a bovine papillomavirus regulatory gene. J Virol. 1993; 67(7):3720-9. PMC: 237735. DOI: 10.1128/JVI.67.7.3720-3729.1993. View