Chapter 7 : Activities of the Transforming Proteins of Human Papillomaviruses

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Activities of the Transforming Proteins of Human Papillomaviruses, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818289/9781555811303_Chap07-1.gif /docserver/preview/fulltext/10.1128/9781555818289/9781555811303_Chap07-2.gif


This chapter deals with viruses which infect the genital tract, although viruses that infect in this region can also infect the oral cavity. Human papillomaviruses (HPVs) are the etiological agents of various lower genital tract cancers, which are important globally. The chapter describes the properties of HPV-16 E5, E6, and E7 and suggests ways in which they might collectively induce S phase in epithelial cells that are being programmed for terminal differentiation. Reference will be made to other HPVs where appropriate, and some comparisons with bovine papillomaviruses (BPVs) are made, especially when discussing the properties of E5. The first section deals with the E6 proteins, its interaction with cellular proteins, and the possible consequences of these interactions with regard to HPV life cycle. The second and third sections deal with E7 proteins and E5 proteins, respectively. E6, a multifunctional HPV protein, has been shown to activate transcription from some promoters and inhibit from others and binds to at least two cellular proteins, E6-associated protein (E6AP) and E6 binding protein (E6BP). The HPV E7 protein plays a critical role in altering the cellular environment for the benefit of viral replication. The E5 gene of most HPVs is located just downstream of the E2 open reading frame. The E5 proteins from both HPV-16 and BPV-1 also bind to the 16-kDa subunit of the vacuolar ATPase. The chapter provides a summary of the action of E6, E7, and E5 on keratinocyte differentiation and cell cycle progression.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7

Key Concept Ranking

Simian virus 40
Cottontail rabbit papillomavirus
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Diagram of HPV-16 E6 and some of the mutations used in two studies to determine the domains of E6 important for binding to p53. The mutations are shown on the top line, and the percentage binding is given in parentheses for each study as indicated. The data as indicated are from references (above the box) and (below the box). A more complete description of the E6 mutations and p53 binding can be found in reference .

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Diagrammatic representation of the HPV-16 E7 protein and the three domains CR1, CR2, and CR3. The known functions of each domain are indicated, and the cellular proteins which bind to each domain are noted below the diagram.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

The retinoblastoma protein (Rb) represses the transactivation of E2F (panels A and C), and this repression is removed during normal cell cycling at the latter part of the G1 phase of the cell cycle when Rb is phosphorylated (B). Rb binds to the histone deacetylase 1 protein (HDAC-1), which may help in the repression of transcription from an E2F promoter. E7 is known to depress Rb, and it is thought to disrupt the Rb/E2F complex (D). In addition, E7 can bind HDAC-1 and so may derepress by competing away from Rb the inhibitory activity of HDAC-1 (D).

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

(A) Diagram of the binding of the EGF ligand to its receptor, EGFR, and the subsequent pathway of the down-regulation and destruction of receptor and ligand through the lysosomal pathway. In human keratinocytes in culture, about 5% of receptors recycle to the surface of the cell.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

(B) The same pathway but this time in the presence of HPV-16 E5. The effects of E5 are indicated by the direction of the arrows inside the E5 boxes. Thus, for example, acidification of the endosomal compartment is inhibited in the present of E5 as indicated by the arrow, while recycling of the receptor is increased to 40% in the presence of E5.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Androphy, E.,, N. L. Hubbert,, J. T. Schiller,, and D. R. Lowy. 1987. Identification of the HPV-16 E6 protein from transformed mouse cells and human cervical carcinoma cell lines. EMBO J. 6:989992.
2. Angel, P.,, and M. Karin. 1991. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 1072:129157.
3. Antinore, M. J.,, M. J. Birrer,, D. Patel,, L. Nader,, and D. J. McCance. 1996. The human papillomavirus type 16 E7 gene product interacts with and trans-activates the API family of transcription factors. EMBO J. 15:19501960.
4. Armstrong, D. J.,, and A. Roman. 1992. Mutagenesis of human papillomavirus types 6 and 16 E7 open reading frames alters the electrophoretic mobility of the expressed proteins. J. Gen. Virol. 73:12751279.
5. Armstrong, D. J.,, and A. Roman. 1993. The anomalous electrophoretic behavior of the human papillomavirus type 16 E7 protein is due to the high content of acidic amino acid residues. Biochem. Biophys. Res. Commun. 192:13801387.
6. Arroyo, M.,, S. Bagchi,, and P. Raychaudhuri. 1993. Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F-cyclin A complex. Mol. Cell. Biol. 13:65376546.
7. Band, V.,, D. Zajchowki,, V. Kulesa,, and R. Sager. 1990. Human papillomavirus DNAs immortalize normal epithelial cells and reduce their growth factor requirements. Proc. Natl. Acad. Sci. USA 87:463467.
8. Banks, L.,, C. Edmonds,, and K. H. Vousden. 1990. Ability of the HPV16 E7 protein to bind RB and induce DNA synthesis is not sufficient for efficient transforming activity in NIH3T3 cells. Oncogene 5:13831389.
9. Barbosa, M. S.,, C. Edmonds,, C. Fisher,, J. T. Schiller,, D. R. Lowy,, and K. H. Vousden. 1990. The region of the HPV E7 oncoprotein homologous to adenovirus Ela and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. EMBO J. 9:153160.
10. Barbosa, M. S.,, and R. Schlegel. 1989. The E6 and E7 genes of HPV-18 are sufficient for inducing two-stage in vitro transformation of human keratinocytes. Oncogene 4: 15291532.
11. Barbosa, M. S.,, W. C. Vass,, D. R. Lowy,, and J. T. Schiller. 1991. In vitro biological activities of the E6 and E7 genes vary among human papillomaviruses of different oncogenic potential. J. Virol. 65:292298.
12. Bouvard, V.,, G. Matlashewski,, Z. M. Gu,, A. Storey,, and L. Banks. 1994. The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression. Virology 203:7380.
13. Brandsma, J. L.,, Z. H. Yang,, S. W. Barthold,, and E. A. Johnson. 1991. Use of a rapid, efficient inoculation method to induce papillomas by cottontail rabbit papillomavirus DNA shows that the E7 gene is required. Proc. Natl. Acad. Sci. USA 88:48164820.
14. Brehm, A.,, E. A. Miskka,, D. J. McCance,, J. L. Reid,, A. J. Bannister,, and T. Kouzarides. Retinoblastoma recruits histone deacetylase activity to repress transcription. Nature, in press.
15. Brokaw, J. L.,, C. L. Yee,, and K. Munger. 1994. A mutational analysis of the amino terminal domain of the human papillomavirus type 16 E7 oncoprotein. Virology 205: 603607.
16. Bubb, V.,, D. J. McCance,, and R. Schlegel. 1988. DNA sequence of the HPV-16 E5 ORF and the structural conservation of its encoded protein. Virology 163:243246.
17. Burkhardt, A.,, D. DiMaio,, and R. Schlegel. 1987. Genetic and biochemical definition of the bovine papillomavirus E5 transforming protein. EMBO J. 6:23812385.
18. Burkhardt, A.,, M. Willingham,, C. Gay,, K. T. Jeang,, and R. Schlegel. 1989. The E5 oncoprotein of bovine papillomavirus is oriented asymmetrically in Golgi and plasma membranes. Virology 170:334339.
19. Busby-Earle, R. M.,, C. M. Steel,, A. R. Williams,, B. Cohen,, and C. C. Bird. 1994. p53 mutations in cervical carcinogenesis--low frequency and lack of correlation with human papillomavirus status. Br. J. Cancer 69:732737.
20. Cao, L.,, B. Faha,, M. Dembski,, L. H. Tsai,, E. Harlow,, and N. Dyson. 1992. Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F. Nature 355:176179.
21. Chen, J. J.,, C. E. Reid,, V. Band,, and E. J. Androphy. 1995. Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science 269:529531.
22. Chen, P. L.,, D. J. Riley,, Y. Chen,, and W. H. Lee. 1996. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev. 10:27942804.
23. Chen, S. L.,, and P. Mounts. 1990. Transforming activity of E5a protein of human papillomavirus type 6 in NIH 3T3 and C127 cells. J. Virol. 64:32263233.
24. Chesters, P. M.,, and D. J. McCance. 1989. Human papillomavirus types 6 and 16 in cooperation with Ha-ras transform secondary rat embryo fibroblasts. J. Gen. Virol. 70:353365.
25. Chesters, P. M.,, K. H. Vousden,, C. Edmonds,, and D. J. McCance. 1990. Analysis of human papillomavirus type 16 open reading frame E7 immortalizing function in rat embryo fibroblast cells. J. Gen. Virol. 71:449453.
26. Chiba, I.,, M. Shindoh,, M. Yasuda,, Y. Yamazaki,, A. Amemiya,, Y. Sato,, K. Fujinaga,, K. Notani,, and H. Fukuda. 1996. Mutations in the p53 gene and human papillomavirus infection as significant prognostic factors in squamous cell carcinomas of the oral cavity. Oncogene 12:16631668.
27. Ciccolini, F.,, G. Di Pasquale,, F. Carlotti,, L. Crawford,, and M. Tommasino. 1994. Functional studies of E7 proteins from different HPV types. Oncogene 9:26332638.
28. Clemens, K. E.,, R. Brent,, J. Gyuris,, and K. Munger. 1995. Dimerization of the human papillomavirus E7 oncoprotein in vivo. Virology 214:289293.
29. Conrad, M.,, V. J. Bubb,, and R. Schlegel. 1993. The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein. J. Virol. 67:61706178.
30. Conrad, M.,, D. Goldstein,, T. Andresson,, and R. Schlegel. 1994. The E5 protein of HPV-6, but not HPV-16, associates efficiently with cellular growth factor receptors. Virology 200:796800.
31. Comelissen, M.,, H. L. Smits,, M. A. Briet,, J. G. van den Tweel,, A. P. Struyk,, J. van der Noorda,, and J. Schegget. 1990. Uniformity of the splicing pattern of the E6/E7 transcripts in human papillomavirus type 16-transformed human fibroblasts, human cervical premalignant lesions and carcinomas. J. Gen. Virol. 71:12431246.
32. Crook, T.,, J. A. Tidy,, and K. H. Vousden. 1991. Degradation of p53 can be targeted by IIPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell 67:547556.
33. Crook, T.,, and K. H. Vousden. 1992. Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens. EMBO J. 11:39353940.
34. Crook, T.,, D. Wrede,, J. A. Tidy,, W. P. Mason,, D. J. Evans,, and K. H. Vousden. 1992. Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours. Lancet 339:10701073.
35. Crook, T.,, D. Wrede,, and K. H. Vousden. 1991. p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6:873875.
36. Davies, R.,, R. Hicks,, T. Crook,, J. Morris,, and K. Vousden. 1993. Human papillomavirus type 16 E7 associates with a histone HI kinase and with p107 through sequences necessary for transformation. J. Virol. 67:25212528.
37. Defeo-Jones, D.,, G. A. Vuocolo,, K. M. Haskell,, M. G. Hanobik,, D. M. Kiefer,, E. M. McAvoy,, M. Ivey-Hoyle,, J. L. Brandsma,, A. Oliff,, and R. E. Jones. 1993. Papillomavirus E7 protein binding to the retinoblastoma protein is not required for viral induction of warts. J. Virol. 67:716725.
38. Devoto, S. H.,, M. Mudryj,, J. Pines,, T. Hunter,, and J. R. Nevins. 1992. A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex. Cell 68:167176.
39. DiMaio, D.,, D. Guralski,, and J. T. Schiller. 1986. Translation of open reading frame E5 of bovine papillomavirus is required for its transforming activity. Proc. Natl. Acad. Sci. USA 83:17971801.
40. Dyson, N.,, P. Guida,, K. Munger,, and E. Harlow. 1992. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins. J. Virol. 66:68936902.
41.Edmonds, C, and K. H. Vousden. 1989. A point mutational analysis of human papillomavirus type 16 E7 protein. J. Virol. 63:26502656.
42. Etscheid, B. G.,, S. A. Foster,, and D. A. Galloway. 1994. The E6 protein of human papillomavirus type 16 functions as a transcriptional repressor in a mechanism independent of the tumor suppressor protein, p53. Virology 205:583585.
43. Firzlaff, J. M.,, B. Luscher,, and R. N. Eisenman. 1991. Negative charge at the casein kinase II phosphorylation site is important for transformation but not for Rb protein binding by the E7 protein of human papillomavirus type 16. Proc. Natl. Acad. Sci. USA 88:51875191.
44. Foster, S. A.,, G. W. Demers,, B. G. Etscheid,, and D. A. Galloway. 1994. The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest. J. Virol. 68: 56985705.
45. Foster, S. A.,, and D. A. Galloway. 1996. Human papillomavirus type 16 E7 alleviates a proliferation block in early passage human mammary epithelial cells. Oncogene 12: 17731779.
46. Funk, J. O.,, S. Waga,, J. B. Harry,, E. Espling,, B. Stillman,, and D. A. Galloway. 1997. Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev. 11:20902100.
47. Gage, J. R.,, C. Meyers,, and F. O. Wettstein. 1990. The E7 proteins of the nononcogenic human papillomavirus type 6b (HPV-6b) and of the oncogenic HPV-16 differ in retinoblastoma protein binding and other properties. J. Virol. 64:723730.
48. Girard, F.,, U. Strausfeld,, A. Fernandez,, and N. J. Lamb. 1991. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67:11691179.
49. Goldstein, D. J.,, T. Andresson,, J. J. Sparkowski,, and R. Schlegel. 1992. The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions. EMBO J. 11:48514859.
50. Grassman, K.,, S. P. Wilezynski,, N. Cook,, B. Rapp,, and T. Iftner. 1996. HPV6 variants from malignant tumors with sequence alterations in the regulatory region do not reveal differences in the activities of the oncogene promoters but do contain amino acid exchanges in the E6 and E7 proteins. Virology 223:185197.
51. Gu, W.,, J. W. Schneider,, G. Condorelli,, S. Kaushal,, V. Mahdavi,, and B. Nadal-Ginard. 1993. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 72:309324.
52. Gu, Z.,, and G. Matlashewski. 1995. Effect of human papillomavirus type 16 oncogenes on MAP kinase activity. J. Virol. 69:80518056.
53.Halbert, C, G. W. Demers, and D. A. Galloway. 1992. The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J. Virol. 66:21252134.
54. Halpern, A.,, and M. Munger. 1995. HPV-16 E7: Primary Structure and Biological Properties, vol. 2. Theoretical Biology and Biophysics Group, Los Alamos, N. Mex.
55. Heck, D. V.,, C. L. Yee,, P. M. Howley,, and K. Munger. 1992. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc. Natl. Acad. Sci. USA 89:44424446.
56. Hiraiwa, A.,, T. Kiyono,, K. Segawa,, K. R. Utsumi,, M. Ohashi,, and M. Ishibashi. 1993. Comparative study on E6 and E7 genes of some cutaneous and genital papillomaviruses of human origin for their ability to transform 3Y1 cells. Virology 192: 102111.
57. Hu, Q. J.,, N. Dyson,, and E. Harlow. 1990. The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations. EMBO J. 9:11471155.
58. Huang, P. S.,, D. R. Patrick,, G. Edwards,, P. J. Goodhart,, H. E. Huber,, L. Miles,, V. M. Garsky,, A. Oliff,, and D. C. Heimbrook. 1993. Protein domains governing interactions between E2F, the retinoblastoma gene product, and human papillomavirus type 16 E7 protein. Mol. Cell. Biol. 13:953960.
59. Huang, S.,, N. P. Wang,, B. Y. Tseng,, W. H. Lee,, and E. H. Lee. 1990. Two distinct and frequently mutated regions of retinoblastoma protein are required for binding to SV40 T antigen. EMBO J. 9:18151822.
60. Huibregtse, J.,, M. Schneffer,, and P. M. Howley. 1991. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10:41294135.
61. Huibregtse, J.,, M. Schneffner,, and P. M. Howley. 1993. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol. Cell. Biol. 13:49184927.
62. Hwang, E. S.,, T. Nottoli,, and D. Dimaio. 1995. The HPV16 E5 protein: expression, detection, and stable complex formation with transmembrane proteins in COS cells. Virology 211:227233.
63. Iftner, T.,, S. Bierfelder,, Z. Csapo,, and H. Pfister. 1988. Involvement of human papillomavirus type 8 genes E6 and E7 in transformation and replication. J. Virol. 62: 36553661.
64. Ikura, M. 1996. Calcium binding and conformational response in EF-hand proteins. Trends Biochem. Sci. 21:1417.
65. Jewers, R. J.,, P. Hildebrandt,, J. W. Ludlow,, B. Kell,, and D. J. McCance. 1992. Regions of human papillomavirus type 16 E7 oncoprotein required for immortalization of human keratinocytes. J. Virol. 66:13291335.
66. Jones, D. L.,, R. M. Alani,, and K. Munger. 1997. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev. 11: 21012111.
67. Kaelin, W. Gv Jr., M. E. Ewen, and D. M. Livingston. 1990. Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product. Mol. Cell. Biol. 10:37613769.
68. Kell, B.,, J. R. Jewers,, J. Cason,, F. Pkarian,, J. N. Kaye,, and J. M. Best. 1994. Detection of E5 oncoprotein in human papillomavirus type 16-positive cervical scrapes using antibodies raised to synthetic peptides. J. Gen. Virol. 75:24512456.
69. Khleif, S. N.,, J. DeGregori,, C. L. Yee,, G. A. Otterson,, F. J. Kaye,, J. R. Nevins,, and P. M. Howley. 1996. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc. Natl. Acad. Sci. USA 93:43504354.
70. Lamberti, C, L. C., Morrissey, S., R. Grossman,, and E. J. Androphy. 1990. Transcriptional activation by the papillomavirus E6 zinc finger oncoprotein. EMBO J. 9: 19071913.
71. Lechner, M. S.,, and L. A. Laimins. 1994. Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J. Virol. 68:42624273.
72. Lechner, M. S.,, D. H. Mack,, A. B. Finicle,, T. Crook,, K. H. Vousden,, and L. A. Laimins. 1992. Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO J. 11:30453052. (Erratum, EMBO J. 11:4248, 1992.)
73. Leechanachi, P.,, L. Banks,, F. Moreau,, and G. Matlashewski. 1992. The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene 7:1925.
74. Lukas, J.,, H. Muller,, J. Bartkova,, D. Spitkovsky,, A. A. Kjerulff,, P. Jansen-Durr,, M. Strauss,, and J. Bartek. 1994. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin Dl function in G1. J. Cell Biol. 125:625638.
75. Martin, P.,, W. C. Vass,, J. T. Schiller,, D. R. Lowy,, and T. J. Velu. 1989. The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors. Cell 59:2132.
76. Massimi, P.,, and L. Banks. 1997. Repression of p53 transcriptional activity by the HPV E7 proteins. Virology 227:255259.
77. Massimi, P.,, D. Pirn,, A. Storey,, and L. Banks. 1996. HPV-16 E7 and adenovirus Ela complex formation with TATA box binding protein is enhanced by casein kinase II phosphorylation. Oncogene 12:23252330.
78. Mazzarelli, J. M.,, G. B. Atkins,, J. V. Geisberg,, and R. P. Ricciardi. 1995. The viral oncoproteins Ad5 E1A, HPV16 E7 and SV40 TAg bind a common region of the TBP-associated factor-110. Oncogene 11:18591864.
79. McCance, D. J.,, R. Kopan,, E. Fuchs,, and L. A. Laimins. 1988. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc. Natl. Acad. Sci. USA 85:71697173.
80. McIntyre, M. C, M. G. Frattini, S. R. Grossman, and L. A. Laimins. 1993. Human papillomavirus type 18 E7 protein requires intact Cys-X-X-Cys motifs for zinc binding, dimerization, and transformation but not for Rb binding. J. Virol. 67:31423150.
81. McIntyre, M. C, M. N. Ruesch, and L. A. Laimins. 1996. Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107. Virology 215:7382.
82. Meyers, G.,, and E. Androphy. 1995. The E6 Protein, vol. 2. Theoretical Biology and Biophysics Group, Los Alamos, N. Mex.
83. Moran, E.,, and M. B. Mathews. 1987. Multiple functional domains in the adenovirus E1A gene. Cell 48:177178.
84. Munger, K.,, and W. C. Phelps. 1993. The human papillomavirus E7 protein as a transforming and transactivating factor. Biochim. Biophys. Acta 1155:111123.
85. Munger, K.,, B. A. Werness,, N. Dyson,, W. C. Phelps,, E. Harlow,, and P. M. Howley. 1989. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 8:40994105.
86. Munger, K.,, C. L. Yee,, W. C. Phelps,, J. A. Pietenpol,, H. L. Moses,, and P. M. Howley. 1991. Biochemical and biological differences between E7 oncoproteins of the high- and low-risk human papillomavirus types are determined by amino-terminal sequences. J. Virol. 65:39433948.
87. Nead, N.,, L. Baglia,, M. J. Antinore,, J. W. Ludlow,, and D. J. McCance. Rb binds c-Jun and activates transcription: a possible role in keratinocyte differentiation. Submitted for publication.
88. Pagano, M.,, M. Durst,, S. Joswig,, G. Draetta,, and P. Jansen-Durr. 1992. Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells. Oncogene 7:16811686.
89. Pagano, M.,, R. Pepperkok,, F. Verde,, W. Ansorge,, and G. Draetta. 1992. Cyclin A is required at two points in the human cell cycle. EMBO J. 11:961971.
90. Pater, M. M.,, H. Nakshatri,, C. Kisaka,, and A. Pater. 1992. The first 124 nucleotides of the E7 coding sequences of HPV16 can render the HPV11 genome transformation competent. Virology 186:348351.
91. Patrick, D. R.,, A. Oliff,, and D. C. Heimbrook. 1994. Identification of a novel retinoblastoma gene product binding site on human papillomavirus type 16 E7 protein. J. Biol. Chem. 269:68426850.
92. Pei, X. F. 1996. The human papillomavirus E6/E7 genes induce discordant changes in the expression of cell growth regulatory proteins. Carcinogenesis 17:13951401.
93. Pennie, W.,, G. J. Grindlay,, M. Cairney,, and M. S. Campo. 1993. Analysis of the transforming functions of bovine papillomavirus type 4. Virology 193:614620.
94. Petti, L.,, L. A. Nilson,, and D. DiMaio. 1991. Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 10: 845855.
95. Phelps, W. C, K. Munger, C. L. Yee, J. A. Barnes, and P. M. Howley. 1992. Structure-function analysis of the human papillomavirus type 16 E7 oncoprotein. J. Virol. 66: 24182427.
96. Phillips, A. C, and K. H. Vousden. 1997. Analysis of the interaction between human papillomavirus type 16 E7 and the TATA-binding protein, TBP. J. Gen. Virol. 78: 905909.
97. Pirn, D.,, M. Collins,, and L. Banks. 1992. Human papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptor. Oncogene 7:2732.
98. Pirn, D.,, A. Storey,, M. Thomas,, P. Massimi,, and L. Banks. 1994. Mutational analysis of HPV-18 E6 identifies domains required for p53 degradation in vitro, abolition of p53 transactivation in vivo and immortalization of primary BMK cells. Oncogene 9: 18691876.
99. Pusch, O.,, T. Soucek,, E. Wawra,, E. Hengstschlager-Ottnad,, G. Bernaschek,, and M. Hengstschlager. 1996. Specific transformation abolishes cyclin Dl fluctuation throughout the cell cycle. FEBS Lett. 385:143148.
100. Qin, X. Q.,, T. Chittenden,, D. M. Livingston,, and W. G. Kaelin, Jr. 1992. Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 6:953964.
101. Rabson, M. S.,, C. Yee,, Y. C. Yang,, and P. M. Howley. 1986. Bovine papillomavirus type 1 3' early region transformation and plasmid maintenance functions. J. Virol. 60:626634.
102. Rawls, J. A.,, R. Pusztai,, and M. Green. 1990. Chemical synthesis of human papillomavirus type 16 E7 oncoprotein: autonomous protein domains for induction of cellular DNA synthesis and for trans activation. J. Virol. 64:61216129.
103. Reznikoff, C. A.,, T. R. Yeager,, C. D. Belair,, E. Savelieva,, J. A. Puthenveettil,, and W. M. Stadler. 1996. Elevated pl6 at senescence and loss of pl6 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells. Cancer Res. 56:28862890.
104. Sang, B. C, and M. S. Barbosa. 1992. Single amino acid substitutions in "low-risk" human papillomavirus (HPV) type 6 E7 protein enhance features characteristic of the "high-risk" HPV E7 oncoproteins. Proc. Natl. Acad. Sci. USA 89:80638067.
105. Scheffner, M.,, J. M. Huibregtse,, R. D. Vierstra,, and P. M. Howley. 1993. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495505.
106. Scheffner, M.,, B. A. Werness,, J. M. Huibregtse,, A. J. Levine,, and P. M. Howley. 1990. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:11291136.
107. Schiller, J. T.,, W. C. Vass,, K. H. Vousden,, and D. R. Lowy. 1986. E5 open reading frame of bovine papillomavirus type 1 encodes a transforming gene. J. Virol. 57:16.
108. Schlegel, R.,, M. Wade-G1ass,, M. S. Rabson,, and Y. C. Yang. 1986. The E5 transforming gene of bovine papillomavirus encodes a small, hydrophobic polypeptide. Science 233:464467.
109. Schmitt, A.,, J. B. Harry,, B. Rapp,, F. O. Wettstein,, and T. Iftner. 1994. Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1. J. Virol. 68:70517059.
110. Schneider-Gadicke, A.,, and E. Schwarz. 1986. Different human cervical carcinoma cell lines show similar transcription patterns of human papillomavirus type 18 genes. EMBO J. 5:22852292.
111. Schwarz, J. K.,, S. H. Devoto,, E. J. Smith,, S. P. Chellappan,, L. Jakoi,, and J. R. Nevins. 1993. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. EMBO J. 12:10131020.
112. Sedman, S.,, M. S. Barbosa,, W. C. Vass,, N. I. Hubbert,, J. A. Haas,, D. R. Lowy,, and J. T. Schiller. 1991. The full length E6 protein of human papillomavirus type 16 has transforming and transactivating activities and cooperates with E7 to immortalize keratinocytes in culture. J. Virol. 65:48604866.
113. Shulze, A.,, K. Zerfass-Thome,, J. Berges,, S. Middendorp,, P. Jansen-Durr,, and B. Henglein. 1996. Anchorage-dependent transcription of the cyclin A gene. Mol. Cell. Biol. 16:46324638.
114. Snijders, P.,, A. J. C. vandenBrule,, H. F. J. Schrijnemakers,, P. M. C. Raaphorst,, C. J. L. M. Meijer,, and J. M. M. Walboomers. 1992. Human papillomavirus type 33 in a tonsillar carcinoma generates its putative E7 mRNA via two E6* transcript species which are terminated at different early region poly(A) sites. J. Virol. 66:31723178.
115. Sparkowski, J.,, J. Anders,, and R. Schlegel. 1995. E5 oncoprotein retained in the endoplasmic reticulum/cis Golgi still induces PDGF receptor autophosphorylation but does not transform cells. EMBO J. 14:30553063.
116. Steinmann, K. E.,, X. F. Pei,, H. Stoppler,, R. Schlegel,, and R. Schlegel. 1994. Elevated expression and activity of mitotic regulatory proteins in human papillomavirus-immortalized keratinocytes. Oncogene 9:387394.
117. Stoppler, M. C, S. W. Straight, G. Tsao, R. Schlegel, and D. J. McCance. 1996. The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA. Virology 223:251254.
118. Storey, A.,, N. Almond,, K. Osborn,, and L. Crawford. 1990. Mutations of the human papillomavirus type 16 E7 gene that affect transformation, transactivation and phosphorylation by the E7 protein. J. Gen. Virol. 71:965970.
119. Straight, S. W.,, B. Herman,, and D. J. McCance. 1995. The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes. J. Virol. 69:31853192.
120. Straight, S. W.,, P. M. Hinkle,, R. J. Jewers,, and D. J. McCance. 1993. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. J. Virol. 67: 45214532.
121. Takami, Y.,, T. Sasagawa,, T. M. Sudiro,, M. Yutsudo,, and A. Hakura. 1992. Determination of the functional difference between human papillomavirus type 6 and 16 E7 proteins by their 30 N-terminal amino acid residues. Virology 186:489495.
122. Taya, Y. 1997. RB kinases and RB-binding proteins: new points of view. Trends Biochem. Sci. 22:1417.
123. Tommasino, M.,, J. P. Adamczewski,, F. Carlotti,, C. F. Barth,, R. Manetti,, M. Contorni,, F. Cavalieri,, T. Hunt,, and L. Crawford. 1993. HPV16 E7 protein associates with the protein kinase p33CDK2 and cyclin A. Oncogene 8:195202.
124. Valle, G.,, and L. Banks. 1995. The human papillomavirus HPV-6 and HPV-16 E5 proteins co-operate with HPV-16 E7 in the transformation of primary rodent cells. J. Gen. Virol. 76:12391245.
125. Wang, J. Y. 1997. Retinoblastoma protein in growth suppression and death protection. Curr. Opin. Genet. Dev. 7:3945.
126. Werness, B. A.,, A. J. Levine,, and P. M. Howley. 1990. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:7679.
127. Wu, E. W.,, K. E. Clemens,, D. V. Heck,, and K. Munger. 1993. The human papillomavirus E7 oncoprotein and the cellular transcription factor E2F bind to separate sites on the retinoblastoma tumor suppressor protein. J. Virol. 67:24022407.
128. Xiong, Y.,, D. Kuppuswamy,, Y. Li,, E. M. Livanos,, M. Hixon,, A. White,, D. Beach,, and T. D. Tlsty. 1996. Alteration of cell cycle kinase complexes in human papillomavirus E6- and E7-expressing fibroblasts precedes neoplastic transformation. J. Virol. 70: 9991008.
129. Zerfass, K.,, A. Schulze,, D. Spitkovsky,, V. Friedman,, B. Henglein,, and P. Jansen-Durr. 1995. Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J. Virol. 69:63896399.
130. Zerfass-Thome, K.,, A. Schulze,, W. Zwerschke,, B. Vogt,, K. Helin,, J. Bartek,, B. Henglein,, and P. Jansen-Durr. 1997. p27kip1 blocks cyclin E-dependent transactivation of cyclin A gene expression. Mol. Cell. Biol. 17:407415.
131. Zwerschke, W.,, S. Joswig,, and P. Jansen-Durr. 1996. Identification of domains required for transcriptional activation and protein dimerization in the human papillomavirus type-16 E7 protein. Oncogene 12:213220.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error