IntroductionKaposi sarcoma herpesvirus (KSHV) is associated with the pathogenesis of primary effusion lymphoma (PEL), Kaposi sarcoma (KS), and some forms of multicentric Castleman disease (MCD). [1][2][3] Its genome contains an extensive number of pirated cellular homologs involved in subverting critical cellular regulatory processes. 4,5 As a member of the ␥-herpesvirus family, KSHV is characterized by a prolonged latency during which only a subset of its genes are expressed. These latently expressed gene products play important roles in immune evasion, cell proliferation, and inhibition of apoptosis.One of these latently expressed proteins, latency-associated nuclear antigen (LANA), is involved in several cellular processes. It is considered an oncogenic protein because of its ability to dysregulate tumor suppressor pathways associated with p53 and pRb and to transform primary rat embryo fibroblasts in cooperation with the cellular oncogene H-ras. 6,7 Its association with GSK-3␤, an important modulator of the Wnt signaling pathway, leads to accumulation of ␤-catenin and subsequent up-regulation of Tcf/Lefregulated genes. 8 LANA inhibits expression of the reactivation transcriptional activator (RTA/Lyta), which is critical for the switch from latency to lytic reactivation. 9,10 It tethers the viral episome to host chromatin during mitosis, ensuring KSHV DNA gets replicated and episomes are not lost during cellular division. 11-14 LANA also regulates viral as well as cellular gene expression. [6][7][8][15][16][17] Although some of the changes mediated by LANA occur indirectly via activation of ␤-catenin and E2F target genes, direct binding of LANA to DNA also results in transcriptional repression. 18,19 Interactions with corepressors mSin3, SAP30, and CIR, the methyl CpG-binding protein MeCP2, and the histone methyltransferase SUV39H1 are consistent with a direct role for LANA in transcriptional repression. 14,20,21 LANA has been shown to inhibit in vitro histone acetyltransferase activity of CREB-binding protein (CBP) and, more recently, to associate with Dnmt3a, a DNA methyltransferase involved in de novo DNA methylation, supporting a role for LANA in epigenetic gene regulation. 16,22 Transforming growth factor-beta (TGF-␤) is a multifunctional cytokine involved in diverse biologic processes, which include embryonic development, regulation of cell growth, differentiation, hematopoiesis, angiogenesis, immune function, and apoptosis (reviewed by Roberts and Sporn 23 and Massague 24 ). There are 3 isoforms of TGF-␤, each of which binds to the same heterotetrameric complex of type I (T␤RI) and type II (T␤RII) serine/ threonine kinase receptors. Initially, TGF-␤ binds to T␤RII, which leads to the recruitment and activation of T␤RI. Receptor-activated Smads (R-Smads), Smad2 and Smad3, are then phosphorylated by T␤RI and translocate into the nucleus in a complex with Smad4. In the nucleus, the Smad complex binds its cognate binding site as well as several transcription factors, transcriptional activators, or transcri...

Primary effusion lymphoma (PEL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8). Despite having a genotype and gene expression signature of highly differentiated B cells, PEL does not usually express surface or cytoplasmic immunoglobulin (Ig). We show the lack of Oct-2 and OCA-B transcription factors to be responsible, at least in part, for this defect in Ig production. Like Ig genes, ORF50, the key regulator of the switch from latency to lytic reactivation, contains an octamer motif within its promoter. We therefore examined the impact of Oct-2 and OCA-B on ORF50 activation. The binding of Oct-1 to the ORF50 promoter has been shown to significantly enhance ORF50 transactivation. We found that Oct-2, on the other hand, inhibited ORF50 expression and consequently lytic reactivation by competing with Oct-1 for the octamer motif in the ORF50 promoter. Our data suggest that Oct-2 downregulation in infected cells would be favorable to KSHV in allowing for efficient viral reactivation.