An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is implicated causally in the development of several human malignancies, including primary effusion lymphoma (PEL). PEL cells serve as tools for KSHV research, as most of them are latently infected and allow lytic virus replication in response to various stimuli. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is the most potent inducer of lytic KSHV reactivation; nevertheless, the exact mechanism by which it induces reactivation remains unknown. It has previously been reported by our group that the protein kinase C (PKC) delta isoform plays a crucial role in TPA-mediated KSHV reactivation. Here, the activation pathway was dissected and it was demonstrated that TPA induces KSHV reactivation via stimulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Western blot analysis revealed a rapid phosphorylation of ERK1/2. Cells treated with MAPK/ERK inhibitors before TPA addition demonstrated repression of ERK1/2 phosphorylation, which was associated with a block of KSHV lytic-gene expression. This inhibition prevented c-Fos accumulation, yet increased c-Jun phosphorylation. Similar results were obtained in response to rottlerin, a selective PKCdelta inhibitor. Notably, the PKC inhibitor GF 109203X reduced ERK1/2 phosphorylation, c-Fos accumulation, c-Jun phosphorylation and KSHV reactivation. It is proposed that TPA induces KSHV reactivation through at least two arms. The first involves PKCdelta, ERK phosphorylation and c-Fos accumulation, whilst the second requires another PKC isoform that induces the phosphorylation of c-Jun. c-Fos and c-Jun jointly form an active AP-1 complex, which functions to activate the lytic cascade of KSHV.

Kaposi's sarcoma-associated herpesvirus: clinical, diagnostic, and epidemiological aspects.

Kaposi's sarcoma-associated herpesvirus (KSHI) is one of the few viruses proven to be associated with tumorigenesis in humans. Its causal association with all clinical and epidemiological variants of Kaposi's sarcoma (KS) is well established. KSHV is also involved in the pathogenesis of primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease (MCD). Possible associations of KSHV with other clinical settings have been extensively examined. The findings from several of these studies are contradictory and are yet to be resolved. Concentrated effort over the last decade, since the initial discovery of KSHV, led to the development of several experimental systems that resulted in a better comprehension of the biological characteristics of KSHV and set the stage for the understanding of mechainisms by which diseases are induced by the virus. The development of molecular, histological, and serological tools for KSHV diagnosis allowed researchers to track the transmission and to study the epidemiology of KSHV. These assays have been applied, in particular in ambiguous cases, in order to confirm clinically and pathologically based diagnoses. Here, we review the advances in the clinical, experimental, diagnostic, and epidemiological research of KSHV.

Role of protein kinase C delta in reactivation of Kaposi's sarcoma-associated herpesvirus.

TPA (12-O-tetradecanoylphorbol-13-acetate), a well-known activator of protein kinase C (PKC), can experimentally induce reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) in certain latently infected cells. We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA. Translocation of the PKCdelta isoform was evident shortly after TPA stimulation. Overexpression of the dominant-negative PKCdelta mutant supported an essential role for the PKCdelta isoform in virus reactivation, yet overexpression of PKCdelta alone was not sufficient to induce lytic reactivation of KSHV, suggesting that additional signaling molecules participate in this pathway.

Familial clustering of classic Kaposi sarcoma.

It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus (KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case.