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The inflammatory kinase MAP4K4 promotes reactivation of Kaposi's sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells.
PLoS Pathog ; 9(11): e1003737, 2013.
Article em En | MEDLINE | ID: mdl-24244164
Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma de Kaposi / Ativação Viral / Regulação Enzimológica da Expressão Gênica / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Herpesvirus Humano 8 / Células Endoteliais / Peptídeos e Proteínas de Sinalização Intracelular / Proteínas de Neoplasias Limite: Female / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma de Kaposi / Ativação Viral / Regulação Enzimológica da Expressão Gênica / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Herpesvirus Humano 8 / Células Endoteliais / Peptídeos e Proteínas de Sinalização Intracelular / Proteínas de Neoplasias Limite: Female / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article