Skip to main content

Role of the ubiquitin system and tumor viruses in AIDS-related cancer

Abstract

Tumor viruses are linked to approximately 20% of human malignancies worldwide. This review focuses on examples of human oncogenic viruses that manipulate the ubiquitin system in a subset of viral malignancies; those associated with AIDS. The viruses include Kaposi's sarcoma herpesvirus, Epstein-Barr virus and human papilloma virus, which are causally linked to Kaposi's sarcoma, certain B-cell lymphomas and cervical cancer, respectively. We discuss the molecular mechanisms by which these viruses subvert the ubiquitin system and potential viral targets for anti-cancer therapy from the perspective of this system.

Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Introduction

Viruses are etiologically linked to approximately 20% of all human malignancies worldwide and much of what we know today about the molecular mechanisms of oncogenesis has come from the study of tumor viruses. The means by which viruses subvert the ubiquitin proteasome system (UPS) is a relatively new area of inquiry. The study of the interactions between viruses and this system not only furthers knowledge of how viruses work, but also often offers shortcuts to understanding cellular processes in general. Though the infectious nature of viruses distinguishes them from other oncogenic factors, it is the adaptation of tumor viruses, mainly DNA viruses, over millennia of co-evolution with their hosts to persistence within these hosts that make the viruses an ideal focus for study of cellular mechanisms reviewed briefly here. This perspective is valid because the immense array of normal intracellular regulatory mechanisms is for the most part intact in latently infected cells, even when they become neoplastic. This symbiosis between virus and cell is mirrored by the fact that in most infected individuals tumors do not develop, and in most instances many years pass between initial infection and appearance of a tumor. The host immune system generally keeps viral infection under control; however, conditions such as acquired immune deficiency syndrome (AIDS) elevate the risk of virus-associated malignancies dramatically [14].

Although human immunodeficiency virus (HIV), the cause of AIDS, itself does not have oncogenic properties, the profound immunodeficiency it causes creates a favorable environment for the development of cancer. All HIV-infected patients are at increased risk of developing several types of cancer, particularly in the later stages of AIDS. Despite highly active anti-retroviral therapy (HAART) being widely employed in developed countries, malignancy in this population is still a leading cause of morbidity and mortality [2, 5, 6].

Among the heterogeneous types of cancer associated with AIDS are Kaposi's sarcoma, immunoblastic B-cell lymphomas and an increased incidence of cervical and anal carcinoma [7, 8]. Three human oncogenic viruses are involved causally: Kaposi's sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV) and human papilloma virus (HPV) [9, 10].

AIDS-related malignancies represent only a small portion of all virus-associated human cancers. The consistency of association between a given virus and a specific malignancy ranges from essentially 100% to as low as 15% depending on the virus, the cancer and other factors [11]. Since the UPS regulates diverse cellular functions, including transcription, stress responses, cell cycle, cellular differentiation, angiogenesis, antigen processing and DNA repair [12], it is inevitably involved in oncogenesis induced by all the human tumor viruses [13, 14].

Here we discuss several examples of how three tumor viruses manipulate the UPS in AIDS-associated viral malignancies, as well as provide perspectives on UPS-directed agents that might offer pathways to therapeutic intervention in these diseases.

Kaposi's sarcoma and KSHV

The search for a transmissible infectious agent as the cause of Kaposi's sarcoma led to the discovery in 1994 of KSHV, so far the newest member of the group of identified human oncogenic viruses [1517]. Even though the incidence of Kaposi's sarcoma has fallen since the introduction of HAART, it is still the most common cancer associated with AIDS [1821].

The ability to evade immune responses is crucial for long-term survival of viruses in the host. Oncogenic viruses make use of diverse strategies in achieving survival; one is the down-regulation of major histocompatibility complex (MHC) class I antigen presentation through the UPS [22, 23].

KSHV encodes several viral products with oncogenic properties, among them two proteins, K3 and K5 (also known as MIR1 and MIR2), that have ubiquitin ligase activity [24, 25]. K3 and K5 recruit E2 enzymes with their N-terminal RING-CH domain [25]. Either direct or indirect interactions between the transmembranes of K3 and K5 and MHC class I molecules ultimately lead to the ubiquitylation of lysine residues present in the MHC class I intracytoplasmic tail [25, 26]. Ubiquitylated MHC class I molecules are then endocytosed and degraded by the lysosome [25, 27, 28]. A recent report indicates that K3, but not K5, can promote down-regulation of MHC class I molecules lacking lysine residues in their intracytoplasmic domains [29]. Another study argues that lysine 63-linked ubiquitylation of MHC class I molecules is necessary for their efficient K3 ubiquitin ligase-mediated endolysosomal degradation [30].

Besides K3 and K5, another KSHV product, the immediate-early transcriptional transactivator RTA, is reported to encode E3 ubiquitin ligase activity [31]. RTA-dependent ubiquitylation of interferon regulatory factor 7 (IRF7), a key inducer of interferon-stimulated genes (ISGs), could target it for ubiquitin-dependent proteasomal degradation [31], thus dampening innate immune responses to the infection.

B-cell lymphomas and EBV

Several decades of intensive studies on EBV, the first human oncogenic virus discovered, have revealed its association with a variety of malignant diseases [11, 3237], including B-cell lymphomas associated with acquired and innate immunosuppressive conditions [3842].

The EBV product EBNA1 represents an interesting example of how a virus evades immune system responses. EBNA1 is a nuclear protein that binds to EBV episomes and is required for maintenance of latency by the virus [34]. This viral protein contains repeats of Gly-Ala residues that prevent its proteasomal degradation and, additionally, sequester cleaved viral products in a cytoplasmic compartment, rendering them inaccessible for presentation by MHC class I molecules [43]. Although EBNA1 is not the only viral protein expressed during EBV latency, its resistance to UPS-dependent degradation creates a perfect camouflage to prevent recognition by the immune system [4345].

Like other tumor viruses, EBV demonstrates its oncogenic potential by redirecting cell signaling pathways. Recent studies reveal ways in which EBV can manipulate different components of the UPS. For example, in B-cells its major oncogenic product, latent membrane protein 1 (LMP1), inhibits Siah-1 ubiquitin ligase to rescue the oncogenic factor β-catenin from proteasomal degradation [46, 47]. In contrast, in epithelial cells LMP1 activates the same ubiquitin ligase, the targets of which in this case are prolyl hydroxylases (PHDs) [48]. These enzymes mark hypoxia-inducible factor-1α (HIF1α for degradation by the UPS. The stability of PHD 1 and PHD 3 is regulated by both Siah-1 and Siah-2 ubiquitin ligases [49]. The result of LMP1-dependent Siah up-regulation in epithelial cells is that HIFα levels are increased and become active HIFα-responsive genes [48, 50]. These are recent observations and physiological reasons for the distinct functional roles of Siah ubiquitin ligases in the different cell types are unknown.

Another EBV latent membrane protein, 2A (LMP2A), acts as a surrogate B-cell receptor by providing constitutive signaling required for B-cell development and survival [51]. LMP2A signaling appears to be regulated in B-cells by association with members of the HECT domain-containing Nedd4 family of ubiquitin ligases [52, 53] and likely utilizes ubiquitin-mediated degradation through the proteasome complex to regulate the strength of its own signal. Such processes could allow LMP2A to modulate B-cell pathways such as differentiation, activation or survival [51].

A further EBV latent antigen, EBNA 3C, targets the tumor suppressor pRb for proteasome-dependent degradation through the well known SCFSkp2 ubiquitin ligase in different systems including B-cells [54]. Besides directing ubiquitylation that leads to proteasomal degradation, EBV can also affect the regulatory lysine 63 ubiquitylation of IRF7 (the master regulator of type I IFN responses), which leads to its activation instead of degradation [55].

Cervical carcinoma and HPV

While Kaposi's sarcoma and B-cell lymphoma are the main viral malignancies associated with AIDS, and their connection with HIV infection are hallmarks of the condition, the association between HIV/AIDS and cervical and anal cancer is less obvious [56, 57]. However, in 1993 a revised classification system for HIV infection listed invasive cervical cancer as one of the AIDS-defining malignancies [58], and there is growing evidence that HIV infection is associated with increased prevalence and severity of HPV-containing malignant cervical lesions [9, 59, 60].

More than 95% of all cervical carcinomas contain at least one copy of one of the HPV genotypes 16 & 18 as well as other types that pose a high risk for the malignancy [61]. The HPV E6 and E7 genes are the only viral genes that are retained and expressed in tumor tissue, and their role in HPV-induced carcinogenesis is well established [6163]. Both proteins cause down-regulation of crucial tumor suppressors; E6 inhibits p53 [6468] and E7 inactivates the retinoblastoma family proteins (pRb) [6972]. Both E6 and E7 utilize the UPS to target these proteins for degradation and thus inactivation [73]. These interactions are recognized as classic oncogenic mechanisms; they operate in place of mutation of p53 and pRb.

HPV E6 recruits E6-associated protein (E6-AP), now recognized to be an E3 ligase; this E6-E6-AP complex then binds to p53, resulting in E6-AP-mediated ubiquitylation and proteasomal degradation of p53 [67, 74, 75]. From the perspective of cancer cell biology, this interaction is of interest because the virus product alters endogenous substrate specificity; normally, p53 is a target for Mdm2 ubiquitin ligase-mediated ubiquitylation and degradation [76, 77].

The mechanism of E7-induced proteasomal degradation of pRb is still unclear [73, 78]. One possibility is that E7 recruits a cellular ubiquitin ligase that targets pRb for ubiquitylation and subsequent degradation. This model is supported by the finding that co-expression of pRb with the Rb-binding-deficient E7 mutant causes a consistent increase in pRb-induced contact-inhibited cell growth in culture [79]. Another possibility is that E7 could function as an adaptor between pRb and the proteasome, thereby targeting pRb directly to the proteasome without prior ubiquitylation, since it has been reported that E7 interacts with the ATPase subunit of the 19S regulatory complex of the 26S proteasome [80].

Disease models, knockouts and assays

Animal models that mimic human cancers caused by viruses are obviously important for understanding the tumor biology of AIDS-associated malignancies, as well as for evaluating the effect of potential anti-tumor and antiviral drugs. Although there is currently still no animal model that accurately represents KSHV, EBV or HPV pathogenesis, mouse models have been established that attempt to address specific factors known to contribute to the development of the diseases. For example, murine gammaherpesvirus 68 (γHV-68) is used as a rodent model to help understand the pathogenesis of EBV and KSHV. Several reviews of γHV-68 have documented advances made toward understanding the pathogenesis of AIDS-associated malignancies in the context of these two human viruses [8183].

Another approach is the transplantation of human tumor tissue to mice with severe combined immunodeficiency disease (SCID), which provides valuable models for viral carcinogenesis and also demonstrates the strict species barrier for infection by human viruses [8487].

As for the roles of the UPS in virus-related cancers, cultured cell lines are still the primary model used at present to study the relations between viral oncogenes and the components of the UPS.

Crucial proof of the transforming potential of KSHV came from de novo infection of cultured bone marrow (microvascular) endothelial cells and human umbilical vein endothelial cells (HUVECs). KSHV infection conferred long-term survival of both cell types and anchorage-independent growth of HUVECs [88]. Continuous KSHV infection and also conditional, productive viral replication in cells cultured from primary effusion lymphoma (PEL) (a rare B-cell non-Hodgkin's lymphoma) [89] provide additional models.

The ability of EBV to immortalize normal human B-lymphocytes in vitro and to transform them into lymphoblastoid cell lines (LCLs) generates a cell-culture model of AIDS-associated EBV lymphomas [90]. Virus-containing B-lymphoblastoid cell lines that have been derived from primary tumors are also suitable as in vitro model systems [91].

Numerous cell lines infected with HPV serve as model cell culture systems to study different aspects of tumorigenesis, but perhaps the most relevant system for evaluating the transforming potential of the HPV oncoproteins is immortalization of primary human keratinocytes, which are the natural host cells of this virus in vivo[92]. HPV-immortalized cells are not tumorigenic in nude mice, although they display altered growth and differentiation.

Due to the oncogenic properties of HPV E6 and E7, these proteins have been the focus of most studies on cervical carcinogenesis [64, 9395]. Although the majority of the studies have been performed using cell culture models, several in vivo mouse model systems have been developed for the study of HPV-dependent carcinogenesis [96].

Disease targets and ligands

Both HPV E6 and E7 dysregulate the UPS so that there is down-regulation of the tumor suppressors p53 and pRb. Since both E6 and E7 are immunogenic, these viral products present potential targets for therapeutic vaccines [97101].

As the UPS is closely involved in the regulation of numerous signaling pathways in tumor cells, it has in the last several years become an attractive target for anti-cancer therapy. The use of proteasome inhibitors to block the final stage in the UPS, proteolysis in the proteasome, presents the opportunity to manipulate intracellular processes in cancer cells for tangible benefit [102106]. Yet, the functional activity of the UPS is crucial for normal cell function; blockade of protein degradation by proteasome inhibitors causes accumulation of misfolded or damaged proteins, which in turn leads to cell death [107, 108]. At the same time, there is much evidence that some proteasome inhibitors are more cytotoxic to proliferating malignant cells than to normal quiescent cells [109].

The first of this new proteasome-inhibiting class of drugs to be on the market, bortezomib (Velcade, formerly known as PS-341), shows promising results in clinical trials with different types of cancer specifically by inhibiting the oncogenic NF-κB signaling pathway [110, 111]. Since UPS-dependent degradation of IκB leads to NF-κB activation (as observed in most known malignancies including those that are AIDS-related [112]), bortezomib could be a candidate for the treatment of the virus-related cancers. In in vitro studies, bortezomib has demonstrated activity against a variety of malignancies by inducing apoptosis in cancer cells and increasing sensitivity of tumor cells to radiation or chemotherapy [113]. Since bortezomib is proving to be highly efficient for treatment of multiple myeloma and also shows promise for lymphoid cancers [113, 114], it could be useful in the treatment of EBV-induced B-lymphomas, which are the second most common AIDS-related malignancy.

Since latent infection with these three DNA viruses is the basis for tumorigenesis, induction of the viral lytic cycle, leading to death of virus-infected malignant cells, is a potential antiviral strategy [115, 116]. Recent study shows that bortezomib induces KSHV lytic gene expression in vitro in two latently KSHV-infected lymphoma cell lines [117]. This result suggests that the UPS regulates viral reactivation and that proteasome inhibitors could have similar effects on other latently infected virus-associated malignant cells.

Also, targeting of other steps of the UPS, such as specific ubiquitin ligases or deubiquitylating enzymes, could produce more selective effects since ubiquitylating and deubiquitylating complexes specifically bind to potential substrates. KSHV ubiquitin ligases K3 and K5 could be good examples of such targets.

Next frontiers

The effect of bortezomib and other proteasome inhibitors in virus-associated malignancies needs to be defined further. Viral products themselves are closely involved in UPS-dependent regulation and therefore the effects of proteasome inhibitors can be unexpected. For instance, it has been shown on one hand that proteasome inhibitors inhibit HIV budding [118] and on the other hand that inhibition of proteasome function can enhance HIV-1 infection [119].

Generally, present knowledge of how UPS modulators affect AIDS/HIV-associated or other virus-related malignancies is very limited and calls for further investigation. Recent information on the relations between tumor viruses and the host cell system is summarized in Table 1.

Table 1 Viral products manipulate the ubiquitin system in AIDS-related cancers. Summarized here is recent information on the relations between tumor viruses and host cell systems. The general strategy through which the ubiquitin system is manipulated, the effector proteins and the host target proteins are indicated for KSHV, EBV and HPV.

Despite the limitations of in vivo model systems for virus-related human malignancies, some (for example, human peripheral blood lymphocytes (hu-PBL) engrafted in SCID mice) could facilitate screening and preliminary testing of proteasome inhibitors.

Finally, there is no doubt that in the broader panorama of other cancers associated with viruses, such as human T-cell lymphotropic virus-1 (HLTV-1: leukemia), hepatitis B and C viruses (HBV and HCV: hepatocellular carcinoma), as well as EBV (nasopharyngeal and gastric carcinomas, Burkitt's and Hodgkin's lymphomas) and HPV (cervical cancer) in non-immunocompromised patients, many aspects of the UPS are at work and will offer targets for therapy.

References

  1. 1.

    Ambinder R. F.: Viruses as potential targets for therapy in HIV-associated malignancies. Hematol Oncol Clin North Am. 2003, 17: 697-702. 10.1016/S0889-8588(03)00045-5. v-vi

    PubMed  Google Scholar 

  2. 2.

    Cheung M. C., Pantanowitz L., Dezube B. J.: AIDS-related malignancies: emerging challenges in the era of highly active antiretroviral therapy. Oncologist. 2005, 10: 412-26. 10.1634/theoncologist.10-6-412.

    CAS  PubMed  Google Scholar 

  3. 3.

    Goedert J. J.: The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol. 2000, 27: 390-401.

    CAS  PubMed  Google Scholar 

  4. 4.

    Shah M. H., Porcu P., Mallery S. R., Caligiuri M. A.: AIDS-associated malignancies. Cancer Chemother Biol Response Modif. 2003, 21: 717-46.

    CAS  PubMed  Google Scholar 

  5. 5.

    Armstrong W., Calabrese L., Taege A. J.: HIV update 2005: origins, issues, prospects, and complications. Cleve Clin J Med. 2005, 72: 73-8.

    PubMed  Google Scholar 

  6. 6.

    Gates A. E., Kaplan L. D.: AIDS malignancies in the era of highly active antiretroviral therapy. Oncology (Williston Park). 2002, 16: 657-65. discussion 665, 668-70

    Google Scholar 

  7. 7.

    Bellan C., De Falco G., Lazzi S., Leoncini L.: Pathologic aspects of AIDS malignancies. Oncogene. 2003, 22: 6639-45. 10.1038/sj.onc.1206815.

    CAS  PubMed  Google Scholar 

  8. 8.

    Bower M., Palmieri C., Dhillon T.: AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis. 2006, 19: 14-9. 10.1097/01.qco.0000200295.30285.13.

    PubMed  Google Scholar 

  9. 9.

    Aoki Y., Tosato G.: Neoplastic conditions in the context of HIV-1 infection. Curr HIV Res. 2004, 2: 343-9. 10.2174/1570162043351002.

    CAS  PubMed  Google Scholar 

  10. 10.

    Hille J. J., Webster-Cyriaque J., Palefski J. M., Raab-Traub N.: Mechanisms of expression of HHV8, EBV and HPV in selected HIV-associated oral lesions. Oral Dis. 2002, 8 (Suppl 2): 161-8. 10.1034/j.1601-0825.2002.00028.x.

    PubMed  Google Scholar 

  11. 11.

    Pagano J. S., Blaser M., Buendia M. A., Damania B., Khalili K., Raab-Traub N., Roizman B.: Infectious agents and cancer: criteria for a causal relation. Semin Cancer Biol. 2004, 14: 453-71. 10.1016/j.semcancer.2004.06.009.

    CAS  PubMed  Google Scholar 

  12. 12.

    Ciechanover A., Orian A., Schwartz A. L.: Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays. 2000, 22: 442-51. 10.1002/(SICI)1521-1878(200005)22:5<442::AID-BIES6>3.0.CO;2-Q.

    CAS  PubMed  Google Scholar 

  13. 13.

    Shackelford J., Pagano J. S.: Tumor viruses and cell signaling pathways: deubiquitination versus ubiquitination. Mol Cell Biol. 2004, 24: 5089-93. 10.1128/MCB.24.12.5089-5093.2004.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. 14.

    Shackelford J., Pagano JS: Targeting of host-cell ubiquitin pathways by viruses. The Ubiquitin-Proteasome System. Edited by: R. L. J Mayer. 2005, Portland Press, London, UK, 41: 139-156.

    Google Scholar 

  15. 15.

    Bubman D., Cesarman E.: Pathogenesis of Kaposi's sarcoma. Hematol Oncol Clin North Am. 2003, 17: 717-45. 10.1016/S0889-8588(03)00044-3.

    PubMed  Google Scholar 

  16. 16.

    Viejo-Borbolla A., Ottinger M., Schulz T. F.: Human herpesvirus 8: biology and role in the pathogenesis of Kaposi's sarcoma and other AIDS-related malignancies. Curr HIV/AIDS Rep. 2004, 1: 5-11. 10.1007/s11904-004-0001-3.

    PubMed  Google Scholar 

  17. 17.

    Viejo-Borbolla A., Schulz T. F.: Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8): key aspects of epidemiology and pathogenesis. AIDS Rev. 2003, 5: 222-9.

    PubMed  Google Scholar 

  18. 18.

    Aversa S. M., Cattelan A. M., Salvagno L., Crivellari G., Banna G., Trevenzoli M., Chiarion-Sileni V., Monfardini S.: Treatments of AIDS-related Kaposi's sarcoma. Crit Rev Oncol Hematol. 2005, 53: 253-65. 10.1016/j.critrevonc.2004.10.009.

    PubMed  Google Scholar 

  19. 19.

    Dittmer D. P., Vahrson W., Staudt M., Hilscher C., Fakhari F. D.: Kaposi's sarcoma in the era of HAART-an update on mechanisms, diagnostics and treatment. AIDS Rev. 2005, 7: 56-61.

    PubMed  Google Scholar 

  20. 20.

    Stebbing J., Sanitt A., Nelson M., Powles T., Gazzard B., Bower M.: A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006, 367: 1495-502. 10.1016/S0140-6736(06)68649-2.

    PubMed  Google Scholar 

  21. 21.

    Vanni T., Sprinz E., Machado M. W., Santana R. D., Fonseca B. A., Schwartsmann G.: Systemic treatment of AIDS-related Kaposi sarcoma: Current status and perspectives. Cancer Treat Rev. 2006

    Google Scholar 

  22. 22.

    Reinstein E.: Immunologic aspects of protein degradation by the ubiquitin-proteasome system. Isr Med Assoc J. 2004, 6: 420-4.

    CAS  PubMed  Google Scholar 

  23. 23.

    Rivett A. J., Hearn A. R.: Proteasome function in antigen presentation: immunoproteasome complexes, Peptide production, and interactions with viral proteins. Curr Protein Pept Sci. 2004, 5: 153-61. 10.2174/1389203043379774.

    CAS  PubMed  Google Scholar 

  24. 24.

    Benichou S., Benmerah A.: The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: “parasites” of the endocytosis pathway]. Med Sci (Paris). 2003, 19: 100-6.

    Google Scholar 

  25. 25.

    Coscoy L., Sanchez D. J., Ganem D.: A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. J Cell Biol. 2001, 155: 1265-73. 10.1083/jcb.200111010.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. 26.

    Sanchez D. J., Coscoy L., Ganem D.: Functional organization of MIR2, a novel viral regulator of selective endocytosis. J Biol Chem. 2002, 277: 6124-30. 10.1074/jbc.M110265200.

    CAS  PubMed  Google Scholar 

  27. 27.

    Coscoy L., Ganem D.: Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci U S A. 2000, 97: 8051-6. 10.1073/pnas.140129797.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. 28.

    Hewitt E. W., Duncan L., Mufti D., Baker J., Stevenson P. G., Lehner P. J.: Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation. Embo J. 2002, 21: 2418-29. 10.1093/emboj/21.10.2418.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. 29.

    Cadwell K., Coscoy L.: Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science. 2005, 309: 127-30. 10.1126/science.1110340.

    CAS  PubMed  Google Scholar 

  30. 30.

    Duncan L. M., Piper S., Dodd R. B., Saville M. K., Sanderson C. M., Luzio J. P., Lehner P. J.: Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. Embo J. 2006, 25: 1635-45. 10.1038/sj.emboj.7601056.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. 31.

    Yu Y., Wang S. E., Hayward G. S.: The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity. 2005, 22: 59-70. 10.1016/j.immuni.2004.11.011.

    CAS  PubMed  Google Scholar 

  32. 32.

    Herrmann K., Niedobitek G.: Epstein-Barr virus-associated carcinomas: facts and fiction. J Pathol. 2003, 199: 140-5. 10.1002/path.1296.

    PubMed  Google Scholar 

  33. 33.

    Raab-Traub N.: Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol. 2002, 12: 431-41. 10.1016/S1044579X0200086X.

    CAS  PubMed  Google Scholar 

  34. 34.

    Rickinson A., Kieff E.: Epstein-Barr virus. Virology. Edited by: P. M. Howley. 2001, Lippincott-Raven Publishers, Philadelphia, Pa, 4rd ed.

    Google Scholar 

  35. 35.

    Tao Q., Young L. S., Woodman C. B., Murray P. G.: Epstein-Barr virus (EBV) and its associated human cancers--genetics, epigenetics, pathobiology and novel therapeutics. Front Biosci. 2006, 11: 2672-713. 10.2741/2000.

    CAS  PubMed  Google Scholar 

  36. 36.

    Young L. S., Murray P. G.: Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 2003, 22: 5108-21. 10.1038/sj.onc.1206556.

    CAS  PubMed  Google Scholar 

  37. 37.

    Young L. S., Rickinson A. B.: Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004, 4: 757-68. 10.1038/nrc1452.

    CAS  PubMed  Google Scholar 

  38. 38.

    Gottschalk S., Rooney C. M., Heslop H. E.: Post-transplant lymphoproliferative disorders. Annu Rev Med. 2005, 56: 29-44. 10.1146/annurev.med.56.082103.104727.

    CAS  PubMed  Google Scholar 

  39. 39.

    Rui L., Goodnow C. C.: Lymphoma and the control of B cell growth and differentiation. Curr Mol Med. 2006, 6: 291-308. 10.2174/156652406776894563.

    CAS  PubMed  Google Scholar 

  40. 40.

    Shimoyama Y., Nakamura S., Asano N., Oshiro A., Oyama T.: [Epstein-Barr virus (EBV)-associated lymphomas and lymphoproliferative disorders]. Nippon Rinsho. 2006, 64 (Suppl 3): 635-8.

    PubMed  Google Scholar 

  41. 41.

    Taylor A. L., Marcus R., Bradley J. A.: Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol. 2005

    Google Scholar 

  42. 42.

    Yin C. C., Medeiros L. J., Abruzzo L. V., Jones D., Farhood A. I., Thomazy V. A.: EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient. Am J Clin Pathol. 2005, 123: 222-8. 10.1309/PH2B-K79H-AVTT-PW13.

    PubMed  Google Scholar 

  43. 43.

    Masucci M. G.: Epstein-Barr virus oncogenesis and the ubiquitin-proteasome system. Oncogene. 2004, 23: 2107-15. 10.1038/sj.onc.1207372.

    CAS  PubMed  Google Scholar 

  44. 44.

    Dantuma N. P., Masucci M. G.: The ubiquitin/proteasome system in Epstein-Barr virus latency and associated malignancies. Semin Cancer Biol. 2003, 13: 69-76. 10.1016/S1044-579X(02)00101-3.

    CAS  PubMed  Google Scholar 

  45. 45.

    Dantuma N. P., Sharipo A., Masucci M. G.: Avoiding proteasomal processing: the case of EBNA1. Curr Top Microbiol Immunol. 2002, 269: 23-36.

    CAS  PubMed  Google Scholar 

  46. 46.

    Jang K. L., Shackelford J., Seo S. Y., Pagano J. S.: Up-regulation of beta-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells. Proc Natl Acad Sci U S A. 2005, 102: 18431-6. 10.1073/pnas.0504054102.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. 47.

    Shackelford J., Maier C., Pagano J. S.: Epstein-Barr virus activates beta-catenin in type III latently infected B lymphocyte lines: association with deubiquitinating enzymes. Proc Natl Acad Sci U S A. 2003, 100: 15572-6. 10.1073/pnas.2636947100.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. 48.

    Kondo S., Seo S. Y., Yoshizaki T., Wakisaka N., Furukawa M., Joab I., Jang K. L., Pagano J. S.: EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res. 2006, 66: 9870-7. 10.1158/0008-5472.CAN-06-1679.

    CAS  PubMed  Google Scholar 

  49. 49.

    Nakayama K., Ronai Z.: Siah: new players in the cellular response to hypoxia. Cell Cycle. 2004, 3: 1345-7.

    CAS  PubMed  Google Scholar 

  50. 50.

    Wakisaka N., Pagano J. S.: Epstein-Barr virus induces invasion and metastasis factors. Anticancer Res. 2003, 23: 2133-8.

    CAS  PubMed  Google Scholar 

  51. 51.

    Portis T., Ikeda M, Longnecker R: Epstein-Barr virus LMP2A: regulating cellular ubiquitination processes for maintenance of viral latency?. Trends Immunol. 2004, 25: 422-6. 10.1016/j.it.2004.05.009.

    CAS  PubMed  Google Scholar 

  52. 52.

    Ikeda M., Ikeda A., Longan L. C., Longnecker R.: The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases. Virology. 2000, 268: 178-91. 10.1006/viro.1999.0166.

    CAS  PubMed  Google Scholar 

  53. 53.

    Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R., Ernberg I., Pawson T.: Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases. Mol Cell Biol. 2000, 20: 8526-35. 10.1128/MCB.20.22.8526-8535.2000.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. 54.

    Knight J. S., Sharma N., Robertson E. S.: Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase. Proc Natl Acad Sci U S A. 2005, 102: 18562-6. 10.1073/pnas.0503886102.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. 55.

    Huye L., Ning S., Pagano JS.: Interferon Regulatory Factor 7 is Activated by a Viral Oncoprotein through RIP-Dependent Ubiquitination. Mol Cell Biol. 2007, 27 (8): 2910-2918. 10.1128/MCB.02256-06.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. 56.

    Goedert J. J., Cote T. R., Virgo P., Scoppa S. M., Kingma D. W., Gail M. H., Jaffe E. S., Biggar R. J.: Spectrum of AIDS-associated malignant disorders. Lancet. 1998, 351: 1833-9. 10.1016/S0140-6736(97)09028-4.

    CAS  PubMed  Google Scholar 

  57. 57.

    Rabkin C. S., Biggar R. J., Baptiste M. S., Abe T., Kohler B. A., Nasca P. C.: Cancer incidence trends in women at high risk of human immunodeficiency virus (HIV) infection. Int J Cancer. 1993, 55: 208-12. 10.1002/ijc.2910550207.

    CAS  PubMed  Google Scholar 

  58. 58.

    1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992, 41: 1-19. [No authors listed]

  59. 59.

    Del Mistro A., Chieco Bianchi L.: HPV-related neoplasias in HIV-infected individuals. Eur J Cancer. 2001, 37: 1227-35. 10.1016/S0959-8049(01)00107-1.

    CAS  PubMed  Google Scholar 

  60. 60.

    Nicol A. F., Fernandes A. T., Bonecini-Almeida Mda G.: Immune response in cervical dysplasia induced by human papillomavirus: the influence of human immunodeficiency virus-1 co-infection -- review. Mem Inst Oswaldo Cruz. 2005, 100: 1-12. 10.1590/S0074-02762005000100001.

    CAS  PubMed  Google Scholar 

  61. 61.

    zur Hausen H.: Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000, 92: 690-8. 10.1093/jnci/92.9.690.

    CAS  PubMed  Google Scholar 

  62. 62.

    de Villiers E. M., Fauquet C., Broker T. R., Bernard H. U., zur Hausen H.: Classification of papillomaviruses. Virology. 2004, 324: 17-27. 10.1016/j.virol.2004.03.033.

    CAS  PubMed  Google Scholar 

  63. 63.

    Palefsky J.: Biology of HPV in HIV infection. Adv Dent Res. 2006, 19: 99-105.

    CAS  PubMed  Google Scholar 

  64. 64.

    Huibregtse J. M., Beaudenon S. L.: Mechanism of HPV E6 proteins in cellular transformation. Semin Cancer Biol. 1996, 7: 317-26. 10.1006/scbi.1996.0041.

    CAS  PubMed  Google Scholar 

  65. 65.

    Mantovani F., Banks L.: The interaction between p53 and papillomaviruses. Semin Cancer Biol. 1999, 9: 387-95. 10.1006/scbi.1999.0142.

    CAS  PubMed  Google Scholar 

  66. 66.

    Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M.: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990, 63: 1129-36. 10.1016/0092-8674(90)90409-8.

    CAS  PubMed  Google Scholar 

  67. 67.

    Thomas M., Pim D., Banks L.: The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene. 1999, 18: 7690-700. 10.1038/sj.onc.1202953.

    CAS  PubMed  Google Scholar 

  68. 68.

    Tommasino M., Accardi R., Caldeira S., Dong W., Malanchi I., Smet A., Zehbe I.: The role of TP53 in Cervical carcinogenesis. Hum Mutat. 2003, 21: 307-12. 10.1002/humu.10178.

    CAS  PubMed  Google Scholar 

  69. 69.

    Dyson N., Howley P. M., Munger K., Harlow E.: The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989, 243: 934-7. 10.1126/science.2537532.

    CAS  PubMed  Google Scholar 

  70. 70.

    Helt A. M., Galloway D. A.: Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis. 2003, 24: 159-69. 10.1093/carcin/24.2.159.

    CAS  PubMed  Google Scholar 

  71. 71.

    Howley P. M., Munger K., Romanczuk H., Scheffner M., Huibregtse J. M.: Cellular targets of the oncoproteins encoded by the cancer associated human papillomaviruses. Princess Takamatsu Symp. 1991, 22: 239-48.

    CAS  PubMed  Google Scholar 

  72. 72.

    Munger K., Werness B. A., Dyson N., Phelps W. C., Harlow E., Howley P. M.: Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. Embo J. 1989, 8: 4099-105.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. 73.

    Scheffner M., Whitaker N. J.: Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. Semin Cancer Biol. 2003, 13: 59-67. 10.1016/S1044-579X(02)00100-1.

    CAS  PubMed  Google Scholar 

  74. 74.

    Talis A. L., Huibregtse J. M., Howley P. M.: The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells. J Biol Chem. 1998, 273: 6439-45. 10.1074/jbc.273.11.6439.

    CAS  PubMed  Google Scholar 

  75. 75.

    Thomas M., Banks L.: Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene. 1998, 17: 2943-54. 10.1038/sj.onc.1202223.

    CAS  PubMed  Google Scholar 

  76. 76.

    Hengstermann A., Linares L. K., Ciechanover A., Whitaker N. J., Scheffner M.: Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci U S A. 2001, 98: 1218-23. 10.1073/pnas.031470698.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. 77.

    Honda R., Tanaka H., Yasuda H.: Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997, 420: 25-7. 10.1016/S0014-5793(97)01480-4.

    CAS  PubMed  Google Scholar 

  78. 78.

    Wang J., Sampath A., Raychaudhuri P., Bagchi S.: Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells. Oncogene. 2001, 20: 4740-9. 10.1038/sj.onc.1204655.

    CAS  PubMed  Google Scholar 

  79. 79.

    Gonzalez S. L., Stremlau M., He X., Basile J. R., Munger K.: Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7. J Virol. 2001, 75: 7583-91. 10.1128/JVI.75.16.7583-7591.2001.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. 80.

    Berezutskaya E., Bagchi S.: The human papillomavirus E7 oncoprotein functionally interacts with the S4 subunit of the 26 S proteasome. J Biol Chem. 1997, 272: 30135-40. 10.1074/jbc.272.48.30135.

    CAS  PubMed  Google Scholar 

  81. 81.

    Gasper-Smith N., Bost K. L.: Initiation of the host response against murine gammaherpesvirus infection in immunocompetent mice. Viral Immunol. 2004, 17: 473-80. 10.1089/vim.2004.17.473.

    CAS  PubMed  Google Scholar 

  82. 82.

    Mistrikova J., Raslova H., Mrmusova M., Kudelova M.: A murine gammaherpesvirus. Acta Virol. 2000, 44: 211-26.

    CAS  PubMed  Google Scholar 

  83. 83.

    Simas J. P., Efstathiou S.: Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol. 1998, 6: 276-82. 10.1016/S0966-842X(98)01306-7.

    CAS  PubMed  Google Scholar 

  84. 84.

    Amado R. G., Mitsuyasu R. T., Zack J. A.: Gene therapy for the treatment of AIDS: animal models and human clinical experience. Front Biosci. 1999, 4: D468-75. 10.2741/Amado.

    CAS  PubMed  Google Scholar 

  85. 85.

    Bonyhadi M. L., Kaneshima H.: The SCID-hu mouse: an in vivo model for HIV-1 infection in humans. Mol Med Today. 1997, 3: 246-53. 10.1016/S1357-4310(97)01046-0.

    CAS  PubMed  Google Scholar 

  86. 86.

    Mosier D. E.: Modeling AIDS in a mouse. Hosp Pract (Minneap). 1996, 31: 41-8. 53-5, 59-60

    CAS  Google Scholar 

  87. 87.

    Trimble J. J., Salkowitz J. R., Kestler H. W.: Animal models for AIDS pathogenesis. Adv Pharmacol. 2000, 49: 479-514.

    CAS  PubMed  Google Scholar 

  88. 88.

    Flore O., Rafii S., Ely S., O'Leary J. J., Hyjek E. M., Cesarman E.: Transformation of primary human endothelial cells by Kaposi's sarcoma-associated herpesvirus. Nature. 1998, 394: 588-92. 10.1038/29093.

    CAS  PubMed  Google Scholar 

  89. 89.

    Dourmishev L. A., Dourmishev A. L., Palmeri D., Schwartz R. A., Lukac D. M.: Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol Mol Biol Rev. 2003, 67: 175-212. 10.1128/MMBR.67.2.175-212.2003. table of contents

    PubMed Central  CAS  PubMed  Google Scholar 

  90. 90.

    Nilsson K.: Human B-lymphoid cell lines. Hum Cell. 1992, 5: 25-41.

    CAS  PubMed  Google Scholar 

  91. 91.

    Drexler H. G., MacLeod R. A.: Leukemia-lymphoma cell lines as model systems for hematopoietic research. Ann Med. 2003, 35: 404-12. 10.1080/07853890310012094.

    CAS  PubMed  Google Scholar 

  92. 92.

    Munger K., Howley P. M.: Human papillomavirus immortalization and transformation functions. Virus Res. 2002, 89: 213-28. 10.1016/S0168-1702(02)00190-9.

    CAS  PubMed  Google Scholar 

  93. 93.

    Finzer P., Aguilar-Lemarroy A., Rosl F.: The role of human papillomavirus oncoproteins E6 and E7 in apoptosis. Cancer Lett. 2002, 188: 15-24. 10.1016/S0304-3835(02)00431-7.

    CAS  PubMed  Google Scholar 

  94. 94.

    McGlennen R. C.: Human papillomavirus oncogenesis. Clin Lab Med. 2000, 20: 383-406.

    CAS  PubMed  Google Scholar 

  95. 95.

    Zwerschke W., Jansen-Durr P.: Cell transformation by the E7 oncoprotein of human papillomavirus type 16: interactions with nuclear and cytoplasmic target proteins. Adv Cancer Res. 2000, 78: 1-29.

    CAS  PubMed  Google Scholar 

  96. 96.

    Eckert R. L., Crish J. F., Balasubramanian S., Rorke E. A.: Transgenic animal models of human papillomavirus-dependent disease (Review). Int J Oncol. 2000, 16: 853-70.

    CAS  PubMed  Google Scholar 

  97. 97.

    Christensen N. D.: Emerging human papillomavirus vaccines. Expert Opin Emerg Drugs. 2005, 10: 5-19. 10.1517/14728214.10.1.5.

    CAS  PubMed  Google Scholar 

  98. 98.

    Govan V. A.: Strategies for human papillomavirus therapeutic vaccines and other therapies based on the e6 and e7 oncogenes. Ann N Y Acad Sci. 2005, 1056: 328-43. 10.1196/annals.1352.016.

    CAS  PubMed  Google Scholar 

  99. 99.

    Kim S. W., Yang J. S.: Human papillomavirus type 16 E5 protein as a therapeutic target. Yonsei Med J. 2006, 47: 1-14.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. 100.

    Mahdavi A., Monk B. J.: Vaccines against human papillomavirus and cervical cancer: promises and challenges. Oncologist. 2005, 10: 528-38. 10.1634/theoncologist.10-7-528.

    CAS  PubMed  Google Scholar 

  101. 101.

    Shillitoe E. J.: Papillomaviruses as targets for cancer gene therapy. Cancer Gene Ther. 2006, 13: 445-50. 10.1038/sj.cgt.7700926.

    CAS  PubMed  Google Scholar 

  102. 102.

    Elliott P. J., Ross J. S.: The proteasome: a new target for novel drug therapies. Am J Clin Pathol. 2001, 116: 637-46. 10.1309/44HW-5YCJ-FLLP-3R56.

    CAS  PubMed  Google Scholar 

  103. 103.

    Kisselev A. F., Goldberg A. L.: Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001, 8: 739-58. 10.1016/S1074-5521(01)00056-4.

    CAS  PubMed  Google Scholar 

  104. 104.

    Monneret C., Buisson J. P., Magdelenat H.: [A new therapy with bortezomib, an oncologic medicinal product of the year 2004]. Ann Pharm Fr. 2005, 63: 343-9.

    CAS  PubMed  Google Scholar 

  105. 105.

    Rajkumar S. V., Richardson P. G., Hideshima T., Anderson K. C.: Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol. 2005, 23: 630-9. 10.1200/JCO.2005.11.030.

    CAS  PubMed  Google Scholar 

  106. 106.

    Tsukamoto S., Yokosawa H.: Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development. Curr Med Chem. 2006, 13: 745-54. 10.2174/092986706776055571.

    CAS  PubMed  Google Scholar 

  107. 107.

    Adams J.: The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004, 4: 349-60. 10.1038/nrc1361.

    CAS  PubMed  Google Scholar 

  108. 108.

    Goldberg A. L., Rock K.: Not just research tools--proteasome inhibitors offer therapeutic promise. Nat Med. 2002, 8: 338-40. 10.1038/nm0402-338.

    CAS  PubMed  Google Scholar 

  109. 109.

    Chauhan D., Hideshima T., Anderson K. C.: Proteasome inhibition in multiple myeloma: therapeutic implication. Annu Rev Pharmacol Toxicol. 2005, 45: 465-76. 10.1146/annurev.pharmtox.45.120403.100037.

    CAS  PubMed  Google Scholar 

  110. 110.

    Richardson P. G., Mitsiades C., Hideshima T., Anderson K. C.: Proteasome inhibition in the treatment of cancer. Cell Cycle. 2005, 4: 290-6.

    CAS  PubMed  Google Scholar 

  111. 111.

    Zavrski I., Jakob C., Schmid P., Krebbel H., Kaiser M., Fleissner C., Rosche M., Possinger K., Sezer O.: Proteasome: an emerging target for cancer therapy. Anticancer Drugs. 2005, 16: 475-81. 10.1097/00001813-200506000-00002.

    CAS  PubMed  Google Scholar 

  112. 112.

    Pande V., Ramos M. J.: NF-kappaB in human disease: current inhibitors and prospects for de novo structure based design of inhibitors. Curr Med Chem. 2005, 12: 357-74.

    CAS  PubMed  Google Scholar 

  113. 113.

    Richardson P. G., Mitsiades C., Hideshima T., Anderson K. C.: Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med. 2006, 57: 33-47. 10.1146/annurev.med.57.042905.122625.

    CAS  PubMed  Google Scholar 

  114. 114.

    Orlowski R. Z., Zeger E. L.: Targeting the proteasome as a therapeutic strategy against haematological malignancies. Expert Opin Investig Drugs. 2006, 15: 117-30. 10.1517/13543784.15.2.117.

    CAS  PubMed  Google Scholar 

  115. 115.

    Israel B. F., Kenney S. C.: Virally targeted therapies for EBV-associated malignancies. Oncogene. 2003, 22: 5122-30. 10.1038/sj.onc.1206548.

    CAS  PubMed  Google Scholar 

  116. 116.

    Gershburg E., Pagano J. S.: Epstein-Barr virus infections: prospects for treatment. J Antimicrob Chemother. 2005, 56: 277-81. 10.1093/jac/dki240.

    CAS  PubMed  Google Scholar 

  117. 117.

    Brown H. J., McBride W. H., Zack J. A., Sun R.: Prostratin and bortezomib are novel inducers of latent Kaposi's sarcoma-associated herpesvirus. Antivir Ther. 2005, 10: 745-51.

    CAS  PubMed  Google Scholar 

  118. 118.

    Schubert U., Ott D. E., Chertova E. N., Welker R., Tessmer U., Princiotta M. F., Bennink J. R., Krausslich H. G., Yewdell J. W.: Proteasome inhibition interferes with gag polyprotein processing, release, and maturation of HIV-1 and HIV-2. Proc Natl Acad Sci U S A. 2000, 97: 13057-62. 10.1073/pnas.97.24.13057.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. 119.

    Wei B. L., Denton P. W., O'Neill E., Luo T., Foster J. L., Garcia J. V.: Inhibition of lysosome and proteasome function enhances human immunodeficiency virus type 1 infection. J Virol. 2005, 79: 5705-12. 10.1128/JVI.79.9.5705-5712.2005.

    PubMed Central  CAS  PubMed  Google Scholar 

Publication history

  1. Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Download references

Acknowledgements

This article has been published as part of BMC Biochemistry Volume 8 Supplement 1, 2007: Ubiquitin-Proteasome System in Disease Part 1. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2091/8?issue=S1.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Joseph S Pagano.

Additional information

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Shackelford, J., Pagano, J.S. Role of the ubiquitin system and tumor viruses in AIDS-related cancer. BMC Biochem 8, S8 (2007). https://doi.org/10.1186/1471-2091-8-S1-S8

Download citation

Keywords

  • Major Histocompatibility Complex Class
  • Human Papilloma Virus
  • Bortezomib
  • Ubiquitin Ligase
  • Proteasome Inhibitor