Abstract
Viral oncogenesis is a multistep process largely depending on the complex interplay between viruses and host factors. The oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Several viral oncoproteins are able to functionally inactivate the tumor suppressor p53, causing deregulated expression of many genes orchestrated by p53, such as those involved in apoptosis, DNA stability, and cell proliferation. The Epstein–Barr virus (EBV) BZLF1, the high-risk human papillomavirus (HPV) E6, and the hepatitis C virus (HCV) NS5 proteins have shown to directly bind to and degrade p53. The hepatitis B virus (HBV) HBx and the human T cell lymphotropic virus-1 (HTLV-1) Tax proteins inhibit p53 activity through the modulation of p300/CBP nuclear factors, while the Kaposi’s sarcoma herpesvirus (HHV8) LANA, vIRF-1 and vIRF-3 proteins have been shown to destabilize the oncosuppressor, causing a decrease in its levels in the infected cells. The large T antigen of the Merkel cell polyomavirus (MCPyV) does not bind to p53 but significantly reduces p53-dependent transcription. This review describes the main molecular mechanisms involved in the interaction between viral oncoproteins and p53-related pathways as well as in the development of therapeutic strategies targeting such interactions.
Highlights
More than 15% of human cancers are caused by infectious agents [1]
Seven human viruses are associated with the majority of pathogen-related tumors, namely, the Epstein–Barr virus (EBV), hepatitis B (HBV) and C (HCV) viruses, human T cell lymphotropic virus 1 (HTLV-1), human papillomaviruses (HPV), Kaposi’s sarcoma herpesvirus (HHV8), and Merkel cell polyomavirus (MCPyV) [2]
The impairment of oncosuppressors by viral factors was first identified by the study of large and small T antigens encoded by the simian vacuolating virus 40 (SV40) demonstrating their ability to inhibit the activity of tumor suppressors such as p53, pRb, p107, and p130/Rb and to cause evasion of apoptosis [5]
Summary
More than 15% of human cancers are caused by infectious agents [1]. Seven human viruses are associated with the majority of pathogen-related tumors, namely, the Epstein–Barr virus (EBV), hepatitis B (HBV) and C (HCV) viruses, human T cell lymphotropic virus 1 (HTLV-1), human papillomaviruses (HPV), Kaposi’s sarcoma herpesvirus (HHV8), and Merkel cell polyomavirus (MCPyV) [2]. Many people become infected by one or more oncoviruses at some point in their lifetime but only a small fraction of infected subjects eventually develop cancer after decades of persistent infection and viral-related insults to the infected cells. During this long coexistence, multiple genetic and epigenetic alterations accumulate in the chronically infected cells, concurring to the multistage process of cancer development. The impairment of oncosuppressors by viral factors was first identified by the study of large and small T antigens encoded by the simian vacuolating virus 40 (SV40) demonstrating their ability to inhibit the activity of tumor suppressors such as p53, pRb, p107, and p130/Rb and to cause evasion of apoptosis [5]. This review describes several mechanisms used by the seven human oncoviruses to directly or indirectly inactivate p53 function
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