Viruses have developed numerous strategies to counteract the host cell defense. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA tumor virus linked to the development of Kaposi's sarcoma, Castleman's disease, and primary effusion lymphoma (PEL). The virus-encoded viral interferon regulatory factor 3 (vIRF-3) gene is a latent gene which is involved in the regulation of apoptosis, cell cycle, antiviral immunity, and tumorigenesis. vIRF-3 was shown to interact with p53 and inhibit p53-mediated apoptosis. However, the molecular mechanism underlying this phenomenon has not been established. Here, we show that vIRF-3 associates with the DNA-binding domain of p53, inhibits p53 phosphorylation on serine residues S15 and S20, and antagonizes p53 oligomerization and the DNA-binding affinity. Furthermore, vIRF-3 destabilizes p53 protein by increasing the levels of p53 polyubiquitination and targeting p53 for proteasome-mediated degradation. Consequently, vIRF-3 attenuates p53-mediated transcription of the growth-regulatory p21 gene. These effects of vIRF-3 are of biological relevance since the knockdown of vIRF-3 expression in KSHV-positive BC-3 cells, derived from PEL, leads to an increase in p53 phosphorylation, enhancement of p53 stability, and activation of p21 gene transcription. Collectively, these data suggest that KSHV evolved an efficient mechanism to downregulate p53 function and thus facilitate uncontrolled cell proliferation and tumor growth.

• MeSH
• apoptóza genetika   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• interferonové regulační faktory genetika   metabolismus   MeSH
• lidé MeSH
• lidský herpesvirus 8 genetika   metabolismus   MeSH
• multimerizace proteinu MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 chemie   genetika   metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein X asociovaný s bcl-2 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• RNA interference MeSH
• serin genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• transfekce MeSH
• ubikvitinace MeSH
• vazba proteinů MeSH
• virové proteiny genetika   metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BAX protein, human MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• inhibitor p21 cyklin-dependentní kinasy MeSH
• interferonové regulační faktory MeSH
• nádorový supresorový protein p53 MeSH
• protein X asociovaný s bcl-2 MeSH
• serin MeSH
• viral interferon regulatory factors MeSH Prohlížeč
• virové proteiny MeSH

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular interferon regulatory factors (IRFs)--viral IRF1 (vIRF1) to vIRF4--and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity.

• MeSH
• apoptóza MeSH
• biologické modely MeSH
• interferonové regulační faktory genetika   imunologie   MeSH
• interferony metabolismus   MeSH
• karcinogeneze MeSH
• lidé MeSH
• lidský herpesvirus 8 genetika   imunologie   patogenita   MeSH
• multigenová rodina MeSH
• signální transdukce MeSH
• virové geny MeSH
• virové proteiny genetika   imunologie   MeSH
• zánět etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• interferonové regulační faktory MeSH
• interferony MeSH
• viral interferon regulatory factors MeSH Prohlížeč
• virové proteiny MeSH

The Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma, body cavity-based lymphoma, and Castleman disease. vIRF-3 is a KSHV latent gene that is critical for proliferation of KSHV-positive lymphoid cells. Furthermore, vIRF-3 contributes to KSHV-associated pathogenesis by stimulating c-Myc transcription activity. Here we show that vIRF-3 can associate with Skp2, a key component of the SCF(skp2) ubiquitin ligase complex. Skp2 is a transcriptional co-factor for c-Myc that was shown to regulate the stability of c-Myc protein as well as c-Myc-dependent transcription. In this study, we show that vIRF-3 binds to the F-box of Skp2 and recruits it to c-Myc-regulated promoters to activate c-Myc-dependent transcription. Additionally, cells overexpressing vIRF-3 exhibit higher levels of c-Myc ubiquitylation, suggesting that ubiquitylation is necessary for c-Myc-mediated transcription. Moreover, vIRF-3 can stabilize the c-Myc protein by increasing its half-life. Collectively, these results indicate that vIRF-3 can effectively manipulate c-Myc stability and function and thus contribute to c-Myc-induced KSHV-associated lymphomagenesis.

• MeSH
• genetická transkripce genetika   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• hyperplazie velkých lymfatických uzlin genetika   metabolismus   virologie   MeSH
• interferonové regulační faktory genetika   metabolismus   MeSH
• lidé MeSH
• lidský herpesvirus 8 genetika   metabolismus   MeSH
• lymfocyty metabolismus   virologie   MeSH
• proteiny asociované s kinázou S-fáze genetika   metabolismus   MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• ubikvitinace genetika   MeSH
• vazba proteinů MeSH
• virové proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferonové regulační faktory MeSH
• MYC protein, human MeSH Prohlížeč
• proteiny asociované s kinázou S-fáze MeSH
• protoonkogenní proteiny c-myc MeSH
• viral interferon regulatory factors MeSH Prohlížeč
• virové proteiny MeSH