This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gao, Q.
Right arrow Articles by Band, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gao, Q.
Right arrow Articles by Band, V.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 1999, p. 733-744, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The E6 Oncoproteins of High-Risk Papillomaviruses Bind to a Novel Putative GAP Protein, E6TP1, and Target It for Degradation

Qingshen Gao,1 Seetha Srinivasan,1 Sarah N. Boyer,2 David E. Wazer,1 and Vimla Band1,2,3,*

Department of Radiation Oncology, New England Medical Center,1 and Department of Biochemistry3 and Genetics Program,2 Tufts University School of Medicine, Boston, Massachusetts 02111

The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6 protein targets the p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53 protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6 oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding protein. This polypeptide, designated E6TP1 (E6-targeted protein 1), exhibits high homology to GTPase-activating proteins for Rap, including SPA-1, tuberin, and Rap1GAP. The mRNA for E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in malignant meningiomas. Importantly, E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6 proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the E6TP1 protein for degradation. Our results identify a novel target for the E6 oncoprotein and provide a potential link between HPV E6 oncogenesis and alteration of a small G protein signaling pathway.

* Corresponding author. Mailing address: Box 824, Department of Radiation Oncology, New England Medical Center, 750 Washington St., Boston, MA 02111. Phone: (617) 636-4776. Fax: (617) 636-6205. E-mail: VBAND{at}opal.tufts.edu.

Molecular and Cellular Biology, January 1999, p. 733-744, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Vos, R. M., Altreuter, J., White, E. A., Howley, P. M. (2009). The Ubiquitin-Specific Peptidase USP15 Regulates Human Papillomavirus Type 16 E6 Protein Stability. J. Virol. 83: 8885-8892 [Abstract] [Full Text]  
  • Kupzig, S., Bouyoucef-Cherchalli, D., Yarwood, S., Sessions, R., Cullen, P. J. (2009). The Ability of GAP1IP4BP To Function as a Rap1 GTPase-Activating Protein (GAP) Requires Its Ras GAP-Related Domain and an Arginine Finger Rather than an Asparagine Thumb. Mol. Cell. Biol. 29: 3929-3940 [Abstract] [Full Text]  
  • Nellore, A., Paziana, K., Ma, C., Tsygankova, O. M., Wang, Y., Puttaswamy, K., Iqbal, A. U., Franks, S. R., Lv, Y., Troxel, A. B., Feldman, M. D., Meinkoth, J. L., Brose, M. S. (2009). Loss of Rap1GAP in Papillary Thyroid Cancer. J. Clin. Endocrinol. Metab. 94: 1026-1032 [Abstract] [Full Text]  
  • Takahashi, M., Rikitake, Y., Nagamatsu, Y., Hara, T., Ikeda, W., Hirata, K.-i., Takai, Y. (2008). Sequential activation of Rap1 and Rac1 small G proteins by PDGF locally at leading edges of NIH3T3 cells.. GENES CELLS 13: 549-569 [Abstract] [Full Text]  
  • Richter, M., Murai, K. K., Bourgin, C., Pak, D. T., Pasquale, E. B. (2007). The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases. J. Neurosci. 27: 14205-14215 [Abstract] [Full Text]  
  • Tsygankova, O. M., Prendergast, G. V., Puttaswamy, K., Wang, Y., Feldman, M. D., Wang, H., Brose, M. S., Meinkoth, J. L. (2007). Downregulation of Rap1GAP Contributes to Ras Transformation. Mol. Cell. Biol. 27: 6647-6658 [Abstract] [Full Text]  
  • Kong, L., Yu, X.-P., Bai, X.-H., Zhang, W.-F., Zhang, Y., Zhao, W.-M., Jia, J.-H., Tang, W., Zhou, Y.-B., Liu, C.-j. (2007). RbAp48 Is a Critical Mediator Controlling the Transforming Activity of Human Papillomavirus Type 16 in Cervical Cancer. J. Biol. Chem. 282: 26381-26391 [Abstract] [Full Text]  
  • Filippova, M., Johnson, M. M., Bautista, M., Filippov, V., Fodor, N., Tungteakkhun, S. S., Williams, K., Duerksen-Hughes, P. J. (2007). The Large and Small Isoforms of Human Papillomavirus Type 16 E6 Bind to and Differentially Affect Procaspase 8 Stability and Activity. J. Virol. 81: 4116-4129 [Abstract] [Full Text]  
  • Zhang, Y., Dasgupta, J., Ma, R. Z., Banks, L., Thomas, M., Chen, X. S. (2007). Structures of a Human Papillomavirus (HPV) E6 Polypeptide Bound to MAGUK Proteins: Mechanisms of Targeting Tumor Suppressors by a High-Risk HPV Oncoprotein. J. Virol. 81: 3618-3626 [Abstract] [Full Text]  
  • McGahren-Murray, M., Terry, N. H.A., Keyomarsi, K. (2006). The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein. Cancer Res. 66: 9744-9753 [Abstract] [Full Text]  
  • Zhang, Y., Gurumurthy, C. B., Kim, J., Bhat, I., Gao, Q., Dimri, G., Lee, S. W., Band, H., Band, V. (2006). The Human Orthologue of Drosophila Ecdysoneless Protein Interacts with p53 and Regulates Its Function.. Cancer Res. 66: 7167-7175 [Abstract] [Full Text]  
  • Zhao, B., Maruo, S., Cooper, A., R. Chase, M., Johannsen, E., Kieff, E., Cahir-McFarland, E. (2006). RNAs induced by Epstein-Barr virus nuclear antigen 2 in lymphoblastoid cell lines. Proc. Natl. Acad. Sci. USA 103: 1900-1905 [Abstract] [Full Text]  
  • Wei, Q. (2005). Pitx2a Binds to Human Papillomavirus Type 18 E6 Protein and Inhibits E6-mediated P53 Degradation in HeLa Cells. J. Biol. Chem. 280: 37790-37797 [Abstract] [Full Text]  
  • Zou, C., Li, J., Bai, Y., Gunning, W. T., Wazer, D. E., Band, V., Gao, Q. (2005). Centrobin: a novel daughter centriole-associated protein that is required for centriole duplication. JCB 171: 437-445 [Abstract] [Full Text]  
  • Tian, X.-x., Rai, D., Li, J., Zou, C., Bai, Y., Wazer, D., Band, V., Gao, Q. (2005). BRCA2 Suppresses Cell Proliferation via Stabilizing MAGE-D1. Cancer Res. 65: 4747-4753 [Abstract] [Full Text]  
  • Schultess, J., Danielewski, O., Smolenski, A. P. (2005). Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets. Blood 105: 3185-3192 [Abstract] [Full Text]  
  • Liu, X., Yuan, H., Fu, B., Disbrow, G. L., Apolinario, T., Tomaic, V., Kelley, M. L., Baker, C. C., Huibregtse, J., Schlegel, R. (2005). The E6AP Ubiquitin Ligase Is Required for Transactivation of the hTERT Promoter by the Human Papillomavirus E6 Oncoprotein. J. Biol. Chem. 280: 10807-10816 [Abstract] [Full Text]  
  • Kelley, M. L., Keiger, K. E., Lee, C. J., Huibregtse, J. M. (2005). The Global Transcriptional Effects of the Human Papillomavirus E6 Protein in Cervical Carcinoma Cell Lines Are Mediated by the E6AP Ubiquitin Ligase. J. Virol. 79: 3737-3747 [Abstract] [Full Text]  
  • Magal, S. S., Jackman, A., Ish-Shalom, S., Botzer, L. E., Gonen, P., Schlegel, R., Sherman, L. (2005). Downregulation of Bax mRNA expression and protein stability by the E6 protein of human papillomavirus 16. J. Gen. Virol. 86: 611-621 [Abstract] [Full Text]  
  • Tarunina, M., Alger, L., Chu, G., Munger, K., Gudkov, A., Jat, P. S. (2004). Functional Genetic Screen for Genes Involved in Senescence: Role of Tid1, a Homologue of the Drosophila Tumor Suppressor l(2)tid, in Senescence and Cell Survival. Mol. Cell. Biol. 24: 10792-10801 [Abstract] [Full Text]  
  • Lee, C., Laimins, L. A. (2004). Role of the PDZ Domain-Binding Motif of the Oncoprotein E6 in the Pathogenesis of Human Papillomavirus Type 31. J. Virol. 78: 12366-12377 [Abstract] [Full Text]  
  • Brown, M. C., Turner, C. E. (2004). Paxillin: Adapting to Change. Physiol. Rev. 84: 1315-1339 [Abstract] [Full Text]  
  • Gewin, L., Myers, H., Kiyono, T., Galloway, D. A. (2004). Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev. 18: 2269-2282 [Abstract] [Full Text]  
  • Lu, Z., Hu, X., Li, Y., Zheng, L., Zhou, Y., Jiang, H., Ning, T., Basang, Z., Zhang, C., Ke, Y. (2004). Human Papillomavirus 16 E6 Oncoprotein Interferences with Insulin Signaling Pathway by Binding to Tuberin. J. Biol. Chem. 279: 35664-35670 [Abstract] [Full Text]  
  • Filippova, M., Parkhurst, L., Duerksen-Hughes, P. J. (2004). The Human Papillomavirus 16 E6 Protein Binds to Fas-associated Death Domain and Protects Cells from Fas-triggered Apoptosis. J. Biol. Chem. 279: 25729-25744 [Abstract] [Full Text]  
  • Chakrabarti, O., Veeraraghavalu, K., Tergaonkar, V., Liu, Y., Androphy, E. J., Stanley, M. A., Krishna, S. (2004). Human Papillomavirus Type 16 E6 Amino Acid 83 Variants Enhance E6-Mediated MAPK Signaling and Differentially Regulate Tumorigenesis by Notch Signaling and Oncogenic Ras. J. Virol. 78: 5934-5945 [Abstract] [Full Text]  
  • Tsygankova, O. M., Feshchenko, E., Klein, P. S., Meinkoth, J. L. (2004). Thyroid-stimulating Hormone/cAMP and Glycogen Synthase Kinase 3{beta} Elicit Opposing Effects on Rap1GAP Stability. J. Biol. Chem. 279: 5501-5507 [Abstract] [Full Text]  
  • Tao, M., Kruhlak, M., Xia, S., Androphy, E., Zheng, Z.-M. (2003). Signals That Dictate Nuclear Localization of Human Papillomavirus Type 16 Oncoprotein E6 in Living Cells. J. Virol. 77: 13232-13247 [Abstract] [Full Text]  
  • Pak, D. T. S., Sheng, M. (2003). Targeted Protein Degradation and Synapse Remodeling by an Inducible Protein Kinase. Science 302: 1368-1373 [Abstract] [Full Text]  
  • Hattori, M., Minato, N. (2003). Rap1 GTPase: Functions, Regulation, and Malignancy. J Biochem 134: 479-484 [Abstract] [Full Text]  
  • Su, L., Hattori, M., Moriyama, M., Murata, N., Harazaki, M., Kaibuchi, K., Minato, N. (2003). AF-6 Controls Integrin-mediated Cell Adhesion by Regulating Rap1 Activation through the Specific Recruitment of Rap1GTP and SPA-1. J. Biol. Chem. 278: 15232-15238 [Abstract] [Full Text]  
  • Singh, L., Gao, Q., Kumar, A., Gotoh, T., Wazer, D. E., Band, H., Feig, L. A., Band, V. (2002). The High-Risk Human Papillomavirus Type 16 E6 Counters the GAP Function of E6TP1 toward Small Rap G Proteins. J. Virol. 77: 1614-1620 [Abstract] [Full Text]  
  • Nguyen, M., Song, S., Liem, A., Androphy, E., Liu, Y., Lambert, P. F. (2002). A Mutant of Human Papillomavirus Type 16 E6 Deficient in Binding {alpha}-Helix Partners Displays Reduced Oncogenic Potential In Vivo. J. Virol. 76: 13039-13048 [Abstract] [Full Text]  
  • Kumar, A., Zhao, Y., Meng, G., Zeng, M., Srinivasan, S., Delmolino, L. M., Gao, Q., Dimri, G., Weber, G. F., Wazer, D. E., Band, H., Band, V. (2002). Human Papillomavirus Oncoprotein E6 Inactivates the Transcriptional Coactivator Human ADA3. Mol. Cell. Biol. 22: 5801-5812 [Abstract] [Full Text]  
  • Filippova, M., Song, H., Connolly, J. L., Dermody, T. S., Duerksen-Hughes, P. J. (2002). The Human Papillomavirus 16 E6 Protein Binds to Tumor Necrosis Factor (TNF) R1 and Protects Cells from TNF-induced Apoptosis. J. Biol. Chem. 277: 21730-21739 [Abstract] [Full Text]  
  • Gao, Q., Kumar, A., Singh, L., Huibregtse, J. M., Beaudenon, S., Srinivasan, S., Wazer, D. E., Band, H., Band, V. (2002). Human Papillomavirus E6-induced Degradation of E6TP1 Is Mediated by E6AP Ubiquitin Ligase. Cancer Res. 62: 3315-3321 [Abstract] [Full Text]  
  • Brinkmann, T., Daumke, O., Herbrand, U., Kuhlmann, D., Stege, P., Ahmadian, M. R., Wittinghofer, A. (2002). Rap-specific GTPase Activating Protein follows an Alternative Mechanism. J. Biol. Chem. 277: 12525-12531 [Abstract] [Full Text]  
  • Degenhardt, Y. Y., Silverstein, S. (2001). Interaction of Zyxin, a Focal Adhesion Protein, with the E6 Protein from Human Papillomavirus Type 6 Results in Its Nuclear Translocation. J. Virol. 75: 11791-11802 [Abstract] [Full Text]  
  • Gewin, L., Galloway, D. A. (2001). E Box-Dependent Activation of Telomerase by Human Papillomavirus Type 16 E6 Does Not Require Induction of c-myc. J. Virol. 75: 7198-7201 [Abstract] [Full Text]  
  • Lee, S.-J., Cho, Y.-S., Cho, M.-C., Shim, J.-H., Lee, K.-A., Ko, K.-K., Choe, Y. K., Park, S.-N., Hoshino, T., Kim, S., Dinarello, C. A., Yoon, D.-Y. (2001). Both E6 and E7 Oncoproteins of Human Papillomavirus 16 Inhibit IL-18-Induced IFN-{{gamma}} Production in Human Peripheral Blood Mononuclear and NK Cells. J. Immunol. 167: 497-504 [Abstract] [Full Text]  
  • Gao, Q., Singh, L., Kumar, A., Srinivasan, S., Wazer, D. E., Band, V. (2001). Human Papillomavirus Type 16 E6-Induced Degradation of E6TP1 Correlates with Its Ability To Immortalize Human Mammary Epithelial Cells. J. Virol. 75: 4459-4466 [Abstract] [Full Text]  
  • Hengstermann, A., Linares, L. K., Ciechanover, A., Whitaker, N. J., Scheffner, M. (2001). Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc. Natl. Acad. Sci. USA 10.1073/pnas.031470698v1 [Abstract] [Full Text]  
  • Degenhardt, Y. Y., Silverstein, S. J. (2001). Gps2, a Protein Partner for Human Papillomavirus E6 Proteins. J. Virol. 75: 151-160 [Abstract] [Full Text]  
  • Nakagawa, S., Huibregtse, J. M. (2000). Human Scribble (Vartul) Is Targeted for Ubiquitin-Mediated Degradation by the High-Risk Papillomavirus E6 Proteins and the E6AP Ubiquitin-Protein Ligase. Mol. Cell. Biol. 20: 8244-8253 [Abstract] [Full Text]  
  • Lee, S. S., Glaunsinger, B., Mantovani, F., Banks, L., Javier, R. T. (2000). Multi-PDZ Domain Protein MUPP1 Is a Cellular Target for both Adenovirus E4-ORF1 and High-Risk Papillomavirus Type 18 E6 Oncoproteins. J. Virol. 74: 9680-9693 [Abstract] [Full Text]  
  • Dulic, V., Beney, G.-E., Frebourg, G., Drullinger, L. F., Stein, G. H. (2000). Uncoupling between Phenotypic Senescence and Cell Cycle Arrest in Aging p21-Deficient Fibroblasts. Mol. Cell. Biol. 20: 6741-6754 [Abstract] [Full Text]  
  • Kao, W. H., Beaudenon, S. L., Talis, A. L., Huibregtse, J. M., Howley, P. M. (2000). Human Papillomavirus Type 16 E6 Induces Self-Ubiquitination of the E6AP Ubiquitin-Protein Ligase. J. Virol. 74: 6408-6417 [Abstract] [Full Text]  
  • Gao, Q., Kumar, A., Srinivasan, S., Singh, L., Mukai, H., Ono, Y., Wazer, D. E., Band, V. (2000). PKN Binds and Phosphorylates Human Papillomavirus E6 Oncoprotein. J. Biol. Chem. 275: 14824-14830 [Abstract] [Full Text]  
  • Hausen, H. z. (2000). Papillomaviruses Causing Cancer: Evasion From Host-Cell Control in Early Events in Carcinogenesis. JNCI J Natl Cancer Inst 92: 690-698 [Abstract] [Full Text]  
  • Park, J.-S., Boyer, S., Mitchell, K., Gilfor, D., Birrer, M., Darlington, G., El Deiry, W., Firestone, G. L., Munger, K., Band, V., Fisher, P. B., Dent, P. (2000). Expression of Human Papilloma Virus E7 Protein Causes Apoptosis and Inhibits DNA Synthesis in Primary Hepatocytes via Increased Expression of p21Cip-1/WAF1/MDA6. J. Biol. Chem. 275: 18-28 [Abstract] [Full Text]  
  • Das, K., Bohl, J., Vande Pol, S. B. (2000). Identification of a Second Transforming Function in Bovine Papillomavirus Type 1 E6 and the Role of E6 Interactions with Paxillin, E6BP, and E6AP. J. Virol. 74: 812-816 [Abstract] [Full Text]  
  • Taylor, W. R., DePrimo, S. E., Agarwal, A., Agarwal, M. L., Schönthal, A. H., Katula, K. S., Stark, G. R. (1999). Mechanisms of G2 Arrest in Response to Overexpression of p53. Mol. Biol. Cell 10: 3607-3622 [Abstract] [Full Text]  
  • Liu, Y., Chen, J. J., Gao, Q., Dalal, S., Hong, Y., Mansur, C. P., Band, V., Androphy, E. J. (1999). Multiple Functions of Human Papillomavirus Type 16 E6 Contribute to the Immortalization of Mammary Epithelial Cells. J. Virol. 73: 7297-7307 [Abstract] [Full Text]  
  • Liu, Y., Tergaonkar, V., Krishna, S., Androphy, E. J. (1999). Human Papillomavirus Type 16 E6-enhanced Susceptibility of L929 Cells to Tumor Necrosis Factor alpha Correlates with Increased Accumulation of Reactive Oxygen Species. J. Biol. Chem. 274: 24819-24827 [Abstract] [Full Text]  
  • Thomas, J. T., Hubert, W. G., Ruesch, M. N., Laimins, L. A. (1999). Human papillomavirus type 31 oncoproteins E6 and E7 are required for the maintenance of episomes during the viral life cycle in normal human keratinocytes. Proc. Natl. Acad. Sci. USA 96: 8449-8454 [Abstract] [Full Text]  
  • Song, S., Pitot, H. C., Lambert, P. F. (1999). The Human Papillomavirus Type 16 E6 Gene Alone Is Sufficient To Induce Carcinomas in Transgenic Animals. J. Virol. 73: 5887-5893 [Abstract] [Full Text]  
  • Tsukamoto, N., Hattori, M., Yang, H., Bos, J. L., Minato, N. (1999). Rap1 GTPase-activating Protein SPA-1 Negatively Regulates Cell Adhesion. J. Biol. Chem. 274: 18463-18469 [Abstract] [Full Text]  
  • Hengstermann, A., Linares, L. K., Ciechanover, A., Whitaker, N. J., Scheffner, M. (2001). Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc. Natl. Acad. Sci. USA 98: 1218-1223 [Abstract] [Full Text]  
  • Butz, K., Denk, C., Ullmann, A., Scheffner, M., Hoppe-Seyler, F. (2000). Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc. Natl. Acad. Sci. USA 97: 6693-6697 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»