KSHV Lytic Genes and Paracrine Neoplasia

Lytic genes are expressed during the phase of the viral life cycle when viral progeny are produced. Consequently, these viral genes are expressed in cells destined to die (lyse). It is therefore generally assumed that lytic genes are not likely to play a significant role in tumorigenesis. However, emerging evidence supports a role for paracrine secretions released by cells expressing KSHV lytic genes in the promotion of KS (Table II).

vGPCR

vGPCR is a G protein-linked receptor (GPCR) that exhibits ligand-independent activities, enabling constitutive signaling through multiple mitogenic and survival pathways. Cells expressing vGPCR also constitutively secrete

Table II Role of KSHV Lytic Genes in Paracrine Neoplasia.

Lytic gene Paracrine mechanism(s) for enhancing cell proliferation vGPCR Induces VEGF transcription and secretion by activating the transcription factor HIF-1 a; induces the transcription and secretion of NFKB-dependent chemokines (e.g., IL-8, Groa, IL-6); activates the transcription factor NFAT leading to upregulation of NFAT-dependent cytokines vIL-6 Binds to gp130 signal transducing subunit of the IL-6R;

promotes VEGF secretion

K1 Induces NFAT activity, leading to expression of several

NFAT-dependent cytokines vMIPs Binds cellular chemokine receptors; proangiogenic angiogenic growth factors and chemokines, including VEGF, interleukin-6 (IL-6), interleukin-8 (IL-8), and growth-related oncogene protein alpha (Groa). Therefore, it can be argued that in KS lesions, the expression of this viral receptor by a subset of infected cells could make a major contribution to KSHV-induced angiogenesis, functioning primarily by paracrine mechanisms.

vIL-6

The KSHV IL-6 homolog (vIL-6) has sequence similarity (25% amino acid identity) to human IL-6. Like its cellular homolog, vIL-6 activates specific JAK/STAT mitogenic signaling pathways by acting on the gp130 signal transducing subunit of the IL-6 receptor. vIL-6 promotes hematopoiesis and acts as an angiogenic factor through the induction of VEGF, suggesting that vIL-6 could play an essential role in the pathogenesis of KS as an autocrine or paracrine factor.

KSHV K1 encodes a transmembrane glycoprotein that interacts with several cellular signal transduction proteins including Vav, p85, and Syk kinase. K1 also induces nuclear factor of activated T cells (NFAT) activity, leading to expression of several cytokines, supportive of a role for this lytic gene in paracrine neoplasia.

vMIPs

Three KSHV genes vMIP-I, vMIP-II, and vMIP-III, are viral chemokines (virokines) that have significant protein sequence similarity to cellular CC chemokines, a super-family of proinflammatory cytokines. Both vMIP-I and vMIP-II are proangiogenic, and all three are agonists for cellular chemokine receptors, consistent with a paracrine role for these virokines in KS progression.

Other lytic genes (e.g., vBcl-2, vIRF-1, Rta, K8) may further contribute to Kaposi's sarcomagenesis by promoting the survival of lytically infected cells. Ongoing efforts examining the roles of these genes in KSHV pathogenesis may provide additional insight into the development of KS.

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