Human papillomaviruses (HPV) have been etiologically linked to human cervical cancer. More than 90% of cervical cancer tissues express two HPV-encoded oncoproteins E6 and E7. Both E6 and E7 proteins possess transformation activity. and together they cooperate to transform primary human keratinocytes, fibroblasts. and epithelial cells. The transforming activity of E7 is associated with its ability to bind the retinoblastoma tumor suppressor protein (Rb). However, the carboxyl-terminal mutants of E7 are also defective for transformation, suggesting that other cellular targets for E7 might exist. We screened a human placenta cDNA library by yeast two-hybrid assay using HPV 16 E7 as a bait and identified the subunit 4 (S4) ATPase of the 26 S proteasome as a novel E7-binding protein. E7 binds to S4 through the carboxyl-terminal zinc binding motif, and the binding is independent of E7 sequences involved in binding to Rb. The interaction between S4 and E7 can be easily detected by in vitro protein binding assays. Moreover, we found that E7 increases the ATPase activity of S4. A recent study has shown that, in epithelial cells, E7 degrades Rb through the 26 S proteasome pathway. We hypothesize that E7 might target Rb for degradation by 26 S proteasome through its interaction with the subunit 4 of the proteasome. Human papillomaviruses (HPV) have been etiologically linked to human cervical cancer. More than 90% of cervical cancer tissues express two HPV-encoded oncoproteins E6 and E7. Both E6 and E7 proteins possess transformation activity. and together they cooperate to transform primary human keratinocytes, fibroblasts. and epithelial cells. The transforming activity of E7 is associated with its ability to bind the retinoblastoma tumor suppressor protein (Rb). However, the carboxyl-terminal mutants of E7 are also defective for transformation, suggesting that other cellular targets for E7 might exist. We screened a human placenta cDNA library by yeast two-hybrid assay using HPV 16 E7 as a bait and identified the subunit 4 (S4) ATPase of the 26 S proteasome as a novel E7-binding protein. E7 binds to S4 through the carboxyl-terminal zinc binding motif, and the binding is independent of E7 sequences involved in binding to Rb. The interaction between S4 and E7 can be easily detected by in vitro protein binding assays. Moreover, we found that E7 increases the ATPase activity of S4. A recent study has shown that, in epithelial cells, E7 degrades Rb through the 26 S proteasome pathway. We hypothesize that E7 might target Rb for degradation by 26 S proteasome through its interaction with the subunit 4 of the proteasome. Human papillomaviruses (HPV) 1The abbreviations used are: HPV, human papilloma virus; CR, conserved region; PCR, polymerase chain reaction; GST, glutathione S-transferase; Rb, retinoblastoma; 3-AT, 3-aminotriazole. have been etiologically linked to human cervical cancer. The HPVs are broadly subdivided into two groups: 1) “low risk” HPVs (HPV 6 and HPV 11), which cause benign squamous epithelial tumors (warts and papillomas); and 2) “high risk” HPVs (HPV 16, HPV 18, HPV 31, and HPV 54), which are associated with malignant tumors. Two high risk HPV early genes, E6 and E7. are selectively retained and expressed at high levels in more than 90% of cervical cancer tissues (reviewed in Refs. 1Mansur C.P. Androphy E.J. Biochim. Biophys. Acta. 1993; 1155: 323-345PubMed Google Scholar, 2Vousden K.H. Semin. Cancer. Biol. 1995; 6: 109-116Crossref PubMed Scopus (101) Google Scholar, 3zur Hausen H. de Villiers E.-M. Annu. Rev. Microbiol. 1994; 48: 427-447Crossref PubMed Scopus (476) Google Scholar). Both E6 and E7 proteins encoded by the high risk HPVs have transformation activities. The E7 oncoprotein by itself can transform established rodent cells such as NIH 3T3 and cooperates with activated Ras oncoprotein or HPV 16 E6 oncoprotein to immortalize primary human keratinocytes, fibroblasts, or epithelial cells in culture (4Halbert C.L. Demers G.W. Galloway D.A. J. Virol. 1991; 65: 473-478Crossref PubMed Google Scholar, 5Hawley-Nelson P. Vousden K.H. Hubbert N.L. Lowy D.R. Schiller J.T. EMBO J. 1989; 8: 3905-3910Crossref PubMed Scopus (785) Google Scholar, 6Münger K. Phelps W.C. Bubb V. Howley P.M. Schlegel R. J. Virol. 1989; 63: 4417-4421Crossref PubMed Google Scholar, 7Reznikoff C.A. Belair C. Savelieva E. Zhai Y. Pfeifer K. Yeager T. Thompson K.J. De Vries S. Brindley C. Newton M.A. Sekhon G. Waldman F. Genes Dev. 1994; 8: 2227-2240Crossref PubMed Scopus (132) Google Scholar, 8Sedman S.A. Barbosa M.S. Vass W.C. Hubbert N.L. Haas J.A. Lowy D.R. Schiller J.T. J. Virol. 1991; 65: 4860-4866Crossref PubMed Google Scholar, 9Wazer D.E. Liu X.-L. Chu Q. Gao Q. Band V. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 3687-3691Crossref PubMed Scopus (176) Google Scholar, 10White A.E. Livanos E.M. Tlsty T.D. Genes Dev. 1994; 8: 666-677Crossref PubMed Scopus (357) Google Scholar). HPV 16 E7 shares sequence homology with other DNA tumor virus oncoproteins such as the adenovirus E1A and SV40 large T antigen. These homologous regions are referred to as conserved region 1 (CR1) and conserved region 2 (CR2). All these oncoproteins including E7 bind the cellular tumor suppressor protein retinoblastoma (Rb) through the CR2 homology region (11DeCaprio J.A. Ludlow J.W. Figge J. Shew J.-Y. Huang C.-M. Lee W.-H. Marsilio E. Paucha E. Livingston D.M. Cell. 1988; 54: 275-283Abstract Full Text PDF PubMed Scopus (1111) Google Scholar, 12Dyson N. Howley P.M. Münger K. Harlow E. Science. 1989; 243: 934-937Crossref PubMed Scopus (2412) Google Scholar, 13Whyte P. Ruley H.E. Harlow E. J. Virol. 1988; 62: 257-265Crossref PubMed Google Scholar). The carboxyl-terminal region of E7 does not share sequence homology with either E1A or T antigen but is highly conserved among all E7 proteins from different HPV serotypes (1Mansur C.P. Androphy E.J. Biochim. Biophys. Acta. 1993; 1155: 323-345PubMed Google Scholar, 2Vousden K.H. Semin. Cancer. Biol. 1995; 6: 109-116Crossref PubMed Scopus (101) Google Scholar, 3zur Hausen H. de Villiers E.-M. Annu. Rev. Microbiol. 1994; 48: 427-447Crossref PubMed Scopus (476) Google Scholar). The carboxyl-terminal region of E7 contains two “Cys-X-X-Cys” motifs that can form a zinc finger. The HPV E6 oncoprotein has two zinc fingers and shares partial amino acid sequence homology with E7 (1Mansur C.P. Androphy E.J. Biochim. Biophys. Acta. 1993; 1155: 323-345PubMed Google Scholar, 2Vousden K.H. Semin. Cancer. Biol. 1995; 6: 109-116Crossref PubMed Scopus (101) Google Scholar). However, a recent study revealed that E6 and E7 zinc binding motifs can form different secondary structures (14Ullman C.G. Haris P.I. Galloway D.A. Emery V.C. Perkins S.J. Biochem. J. 1996; 319: 229-239Crossref PubMed Scopus (44) Google Scholar). The carboxyl-terminal sequences of E7 are also involved in dimerization of the protein (15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar). The interaction with Rb is essential for the transformation function of E7 (1Mansur C.P. Androphy E.J. Biochim. Biophys. Acta. 1993; 1155: 323-345PubMed Google Scholar, 2Vousden K.H. Semin. Cancer. Biol. 1995; 6: 109-116Crossref PubMed Scopus (101) Google Scholar, 6Münger K. Phelps W.C. Bubb V. Howley P.M. Schlegel R. J. Virol. 1989; 63: 4417-4421Crossref PubMed Google Scholar, 15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar, 16Jewers R. Hildebrandt P. Lublow J. Kell B. McCance D. J. Virol. 1992; 66: 1329-1335Crossref PubMed Google Scholar). Mutations in the Rb-binding region severely impair the transformation activity of E7. The HPV E7 protein of low risk HPV is less efficient in binding to Rb and has very weak transformation activity. However, detailed mutagenesis of E7 has revealed that Rb/E7 binding alone is not sufficient because mutations in the carboxyl-terminal sequences of E7, outside the Rb-binding site, also severely impair the transformation function (15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar, 16Jewers R. Hildebrandt P. Lublow J. Kell B. McCance D. J. Virol. 1992; 66: 1329-1335Crossref PubMed Google Scholar). These results suggest that, aside from binding to Rb, other protein-protein interaction(s) are also necessary for E7-mediated transformation. The 26 S proteasome is a large multimeric protein complex, which catalyzes ATP- and ubiquitin-dependent protein degradation in eukaryotic cells (reviewed in Ref. 17Coux O. Tanaka K. Goldberg A.L. Annu. Rev. Biochem. 1996; 65: 801-847Crossref PubMed Scopus (2239) Google Scholar). The 26 S proteasome controls programmed degradation of many critical cell cycle regulatory proteins. For example, programmed degradation of mitotic cyclins (18Glotzer M. Murray A. Kirschner M.W. Nature. 1991; 349: 132-138Crossref PubMed Scopus (1903) Google Scholar), maturation-promoting factor (19Holloway S. Glotzer M. King R. Murray A.W. Cell. 1993; 73: 1393-1402Abstract Full Text PDF PubMed Scopus (489) Google Scholar), and the inhibitor of cyclin-dependent kinase p27 (20Pagano M. Tam S.W Theodoras A.M Beer-Romero P. Del Sal G. Chau V. Yew P.R. Draetta G. Rolfe M. Science. 1995; 269: 682-685Crossref PubMed Scopus (1736) Google Scholar) by 26 S proteasome are crucial for cell cycle progression. In addition, the 26 S proteasome is responsible for signal-dependent maturation of an inactive precursor of the transcription factor NF-κB and proteolysis of its negative regulator I-κB (21Palombella V. Rando O. Golberg A. Maniatis T. Cell. 1994; 78: 773-785Abstract Full Text PDF PubMed Scopus (1922) Google Scholar, 22Scherer D. Brockman J. Chen Z. Maniatis T. Ballard D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11259-11263Crossref PubMed Scopus (502) Google Scholar). The levels of the tumor suppressor proteins Rb (23Boyer S.N. Wazer D.E. Band V. Cancer Res. 1997; 56: 4620-4624Google Scholar) and p53 (24Scheffner M. Werness B. Huibregtse J. Levine A. Howley P.M. Cell. 1990; 63: 1129-1136Abstract Full Text PDF PubMed Scopus (3484) Google Scholar), proto-oncoproteins c-Jun and c-Fos (25Treier M. Staszewski L. Bohmann D. Cell. 1994; 78: 787-798Abstract Full Text PDF PubMed Scopus (847) Google Scholar,26Wang W. Chevray P. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8236-8240Crossref PubMed Scopus (53) Google Scholar), and the regulatory subunit of protein kinase A (27Hegde A. Goldberg A. Schwartz J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 7436-7440Crossref PubMed Scopus (189) Google Scholar) are also regulated by the 26 S proteasome. The 26 S proteasome contains multiple ATPase subunits (19Holloway S. Glotzer M. King R. Murray A.W. Cell. 1993; 73: 1393-1402Abstract Full Text PDF PubMed Scopus (489) Google Scholar). ATP hydrolysis is crucial for protein degradation by 26 S proteasome and is also required for the assembly of the proteasome enzymes CF1, CF2, and CF3. The S4-ATPase is known to be important for the 26 S proteasome function because fission yeasts showed defective proteolysis due to mutation in the mts2 gene, which codes for the yeast homologue of human S4 (28Gordon C. McGurk G. Dillon P. Rosen C. Hastie N.D. Nature. 1993; 366: 355-357Crossref PubMed Scopus (210) Google Scholar). Interestingly, the human S4-ATPase can rescue these mts2 null alleles (28Gordon C. McGurk G. Dillon P. Rosen C. Hastie N.D. Nature. 1993; 366: 355-357Crossref PubMed Scopus (210) Google Scholar). The S4-ATPase, together with TBP-1, MSS1, and SUG1, belongs to a recently described ATPase family (reviewed in Ref. 29Rechsteiner M. Hoffman L. Dubiel W. J. Biol. Chem. 1993; 268: 6065-6068Abstract Full Text PDF PubMed Google Scholar). All these ATPases have an evolutionary conserved ATPase module and partially conserved carboxyl-terminal domains. In contrast, these ATPases have only limited sequence homology in the amino-terminal domains, and it is believed that the variable NH2-terminal regions of these ATPases are involved in regulation of the ATPase activity. Consistent with this idea, it has been shown that deletion of the variable NH2-terminal region of the budding yeast protein Yhs4p, a homologue of human S4, resulted in 4-fold increase of its ATPase activity S. H. N. J. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). that human S4-ATPase with the E7 but not with the E6 revealed that E7 with S4 through its carboxyl-terminal results that the binding of E7 to S4 results in of the S4-ATPase activity. We hypothesize that the E7-mediated increase in S4-ATPase activity is important for the cell cycle regulatory function of E7. The yeast H.E. D. Res. 1994; PubMed Scopus Google Scholar) and P. R. S. 1993; Google Scholar), used in this study either in yeast or in P. R. S. 1993; Google Scholar) with at The HPV 16 and the mutants have been described M. S. P. Cell. Biol. 1993; PubMed Scopus Google Scholar). chain from the and E7 mutants into of the yeast P. R. S. D.A. in A Scholar) in with For the used as the and as the For of the used as The carboxyl-terminal by mutagenesis using the as for E7 but a different by into of The HPV 16 E6 into of the an of the Rb cDNA sequences between and into of the yeast P. R. S. D.A. in A Scholar) in with transcription For this used as the and used as the of all the by DNA by the of to amino into of in with We screened a human placenta cDNA library of proteins between the and cDNA in yeast from the library into with the by transformation as described D. A. Res. 1992; PubMed Scopus Google Scholar). The the and and to with The for 6 at The the and for the activity. In the the into for and for to 6 at in and of that the These but to the from the for the of by by partial DNA and using the GST, and proteins as described M. S. P. Cell. Biol. 1993; PubMed Scopus Google Scholar). The of proteins by by of the proteins by protein The used in the ATPase assay the ATPase described ATPase activity of in the and at for as described S. H. N. J. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). by of of and of the by in 1 acid to the from the K.J. PubMed Google Scholar). the the the from the and by The ATPase as of ATP of S4 All these ATPase in the of assays. ATPase at with in and for by cells in 1 with of for at 4 P. R. S. D.A. in A Scholar). For cell by The proteins to a with E7 and by The to described F. Nature. 1993; Scopus Google Scholar). S4 protein by in vitro in The S4 proteins with proteins the proteins from the by for at in 1 and by We used the yeast two-hybrid assay to novel E7-binding proteins. The assay is the of the yeast from two the and the transcription P. R. S. D.A. in A Scholar). the two proteins the is and can transcription from The yeast used in has two such 1) and 2) of for the of the of these in The has a low of transcription in of to yeast as a of low of an inhibitor of 3-AT, used in all interaction We used the protein as a to a human placenta cDNA The of the protein in the yeast cells by A protein of the detected with the E7 in the of yeast cells, but not in the of the The by itself showed or activity in the yeast cells not and as a bait for the library for the E7-binding we from the library with the bait into the yeast and for The and for of the activity. that 1 from these and partial sequence revealed that of these cDNA for the Rb protein. DNA sequence of cDNA revealed of these with the human S4 of the 26 S proteasome W. K. G. M. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). the S4 subunit of 26 S proteasome has cell cycle regulatory (28Gordon C. McGurk G. Dillon P. Rosen C. Hastie N.D. Nature. 1993; 366: 355-357Crossref PubMed Scopus (210) Google Scholar), we a detailed of the interaction between E7 and S4. the of the interaction between S4 and E7, we the ability of S4 to with the HPV 16 E6 as as with by yeast two-hybrid interaction 1 The to in to the transformation or in the to for from these showed that HPV 16 E7 with S4, HPV 16 E6 showed interaction with S4 1 the of E7 involved in the we used that either the or of E7 The E7 mutants E7 in homology E7 in CR2 homology E7 in CR2 homology E7 mutation in CR2 homology and E7 mutation in carboxyl-terminal zinc These E7 mutants have been for the Rb/E7 interaction and transformation (15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar, 16Jewers R. Hildebrandt P. Lublow J. Kell B. McCance D. J. Virol. 1992; 66: 1329-1335Crossref PubMed Google Scholar, K. Werness N. Phelps W.C. Harlow E. Howley P. EMBO J. 1989; 8: PubMed Scopus Google Scholar). the interaction with the the mutants described in the yeast two-hybrid interaction with either S4 or Rb. In with results from the Rb/E7 interaction in yeast two-hybrid assay showed the sequences in the CR2 homology region of the HPV 16 E7 2 The deletion or the in CR2 region defective in Rb The E7 deletion in the CR2 region outside the Rb-binding with Rb as as E7. The E7 with deletion in homology region and a in the carboxyl-terminal region with the Rb protein. the of E7 mutants used in a assay to the the carboxyl-terminal E7 with mutation in the found to be severely in interaction with S4 Interestingly, this E7 showed interaction with Rb. The other E7 mutants in the and CR2 homology regions with S4 The E7 mutants used in this assay expressed in in yeast cells K. R. J. Münger K. 1996; Scopus Google and not these results suggest that the carboxyl-terminal of E7 is important for the interaction and the involved in Rb/E7 interaction is different from the required for The results from the two-hybrid an interaction between the carboxyl-terminal sequences of E7 and S4 in yeast cells. an interaction between S4 and E7 of yeast we an in assay between the S4 protein in and the proteins. The protein 16 E7 and mutants including and expressed and by of the proteins is shown in A. of these proteins with of S4. the proteins from the and by Interestingly, in with the in the yeast two-hybrid S4 with the but not with the protein and Moreover, S4 with other including and These results showed that E7 can bind to S4 through its carboxyl-terminal sequences independent of yeast protein. The S4 subunit of 26 S proteasome is an with yeast homologue of S4, Yhs4p, have shown that the protein in vitro ATPase activity S. H. N. J. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, W. K. G. M. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). the of E7 binding the S4-ATPase we used the in vitro ATPase assay as described for the protein. We the cDNA amino of the human S4 protein in the to the protein. The protein using The ATPase of the and protein by using as the S. H. N. J. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google also and The ATPase for the of of and the of from the the for the of assay these the protein an ATPase activity in a at the of the showed ATPase activity 4 the of E7 binding the S4 ATPase different of with the ATPase assays. The as in showed that of E7 protein the ATPase activity of alone showed ATPase activity 4 of ATPase activity of revealed that it has a for ATP of and a of of of protein 4 Interestingly, of not the for the S4-ATPase, but to of of protein 4 that E7 binding to of the activity of S4 in The of S4-ATPase activity a of E7, because in a the protein showed the S4-ATPase activity the protein a in amino acid from to showed of S4-ATPase activity The E7 protein in interaction with S4 in in vitro binding assay and in yeast two-hybrid interaction the of of the S4-ATPase activity by this E7 protein a interaction between S4 and E7. A study with the yeast homologue of S4-ATPase, Yhs4p, that the protein a ATPase activity with for ATP of and of of of protein S. H. N. J. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The activity of the S4-ATPase is essential for the function of the 26 S an increase in S4-ATPase activity by E7 is to have an important regulatory the function of the 26 S proteasome. HPV 16 E7 protein has been shown to with the Rb family proteins Rb, and and cyclins such as A and through the sequences in the CR2 However, these only partially for the of E7. For example, the carboxyl-terminal and the amino-terminal regions of E7 protein are critical for its but cellular targets for either of these two have been identified P. Vousden K.H. Hubbert N.L. Lowy D.R. Schiller J.T. EMBO J. 1989; 8: 3905-3910Crossref PubMed Scopus (785) Google Scholar, 15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar, M. Murray A. Kirschner M.W. Nature. 1991; 349: 132-138Crossref PubMed Scopus (1903) Google Scholar, W. Münger C. J. Howley P. J. Virol. 1992; 66: PubMed Google Scholar, S. T. H. A. K. J. Virol. 1990; PubMed Google Scholar). In this using the yeast two-hybrid we identified the S4-ATPase of 26 S proteasome as a novel E7-binding protein. The interaction because HPV with partial sequence homology with E7 to with S4. we that S4 through the carboxyl-terminal of E7. The S4 is the only known cellular target for the carboxyl-terminal region of E7, and with S4 are to in the of this highly conserved of E7. The carboxyl-terminal is involved in dimerization of E7. and it is that S4 binding might with the dimerization of E7 (15McIntyre M.C. Frattini M.G. Grossman S.R. Laimins L. J. Virol. 1993; 67: 3142-3150Crossref PubMed Google Scholar). the of dimerization the of E7 is not it be to the dimerization is by binding of the S4 subunit of 26 S proteasome. The oncoprotein E6 binds and degrades the tumor suppressor p53 through the 26 S proteasome pathway. E6 binds the and which to and degradation of p53 by 26 S proteasome M. Huibregtse R. Howley P.M. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). The E7 oncoprotein has not been shown to in this p53 degradation revealed that E7 binds S4 and the ATPase activity of S4. of the of the S4 revealed that E7 interaction does not the of the S4-ATPase that E7 does not with the of S4. The 4-fold increase in the of S4-ATPase by E7 that E7 can increase the of activity the The ATPases associated with the 26 S proteasome are involved in the assembly of the 26 S proteasome enzymes and proteolysis through the 26 S proteasome. it is not E7 binding might the function of the 26 S be necessary to 26 S proteasome has multiple ATPase and they have been to be involved in degradation of A recent study has shown that the ATPase c-Fos protein for degradation to the 26 S proteasome W. Chevray P. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8236-8240Crossref PubMed Scopus (53) Google Scholar). interaction might E7-binding for proteolysis by the 26 S proteasome. The levels of regulatory proteins are in cells, and of these proteins are known to be regulated through degradation by 26 S proteasome. the important target for E7 protein is the retinoblastoma protein Rb. have shown that the of the E7-binding tumor suppressor Rb protein is in cell D.E. Liu X.-L. Chu Q. Gao Q. Band V. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 3687-3691Crossref PubMed Scopus (176) Google Scholar, 10White A.E. Livanos E.M. Tlsty T.D. Genes Dev. 1994; 8: 666-677Crossref PubMed Scopus (357) Google Scholar). a recent study has shown that, in epithelial cells, E7 degradation of Rb through 26 S proteasome (23Boyer S.N. Wazer D.E. Band V. Cancer Res. 1997; 56: 4620-4624Google Scholar). E7 binds Rb and S4 through independent domains, it is that a is an to the degradation of Rb. The tumor suppressor Rb has been as a regulator of cellular such as cell cycle and be important to the interaction is a crucial in degradation of Rb through the 26 S proteasome pathway. The oncoproteins E6 and E7 the of the tumor p53 and Rb, More than 90% of the human cervical cancer tissues express high levels of these two oncoproteins but Rb and p53 proteins. However, p53 and Rb are in a of human cervical E6 degrades p53 through the 26 S proteasome pathway. is that E7 can also target Rb degradation through the 26 S (23Boyer S.N. Wazer D.E. Band V. Cancer Res. 1997; 56: 4620-4624Google Scholar). These results together that human papillomaviruses have a novel for degradation of crucial tumor suppressor proteins through 26 S proteasome to tumor We are to M. of the of of of for with the S4 cDNA described in this We Y. K. of of at for in the ATPase We P. of and and G. of for the We for
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