KSHV Latent Genes and the Promotion of Cell Proliferation and Survival

Efforts to identify the KSHV gene(s) responsible for the genesis of KS have focused primarily on the latent genes (LANA-1, LANA-2, vCyclin, vFlip, and Kaposin). These genes are expressed in almost all spindle cells in late KS lesions and are therefore expected to play a critical role in the progression of KS. Several recent studies have suggested that many of the KSHV latent genes bear potential for promoting endothelial cell transformation (Table I).

LANA-1 and 2

In addition to maintaining the KSHV episome and ensuring its efficient segregation to progeny cells, LANA-1 has been shown to interact with and inhibit the tumor suppressor proteins p53 and pRB. Similarly, LANA-2 also inhibits

Table I Role for KSHV Latent Genes in Endothelial Cell Immortalization.

Latent gene

Mechanism(s) for enhancing cell proliferation

LANA-1

Interacts with and inhibits the two tumor suppressor

proteins p53 and Rb. Stabilizes b-catenin by

binding to its negative regulator GSK-3b, causing

a cell cycle-dependent nuclear accumulation of

GSK-3b

LANA-2

Interacts with p53, antagonizing p53-mediated

apoptosis

vCyclin

Complexes with cellular cdk6 to phosphorylate and

inactivate the tumor suppressor Rb and the CDK

inhibitor p27, thereby promoting cell cycle

progression

vFlip

Binds to procaspase-8, inhibiting its recruitment and

activation at the death-induced signaling complex,

resulting in diminished Fas-mediated apoptotic

cascade initiation

Kaposin (K12)

Interacts with cytohesin-1, an ARF guanine

nucleotide exchange factor, leading to the

activation of the mitogenic kinase ERK1/2.

p53 and may cooperate with LANA-1 to repress the function of this tumor suppressor protein. More recently, LANA-1 has also been shown to stabilize b-catenin by binding to its negative regulator GSK-3P, causing a cell cycle-dependent nuclear accumulation of GSK-3p. Although neither LANA protein is directly transforming, LANA-1 can prolong the life span of primary human endothelial cells, suggestive of a role for this latent protein in endothelial cell immortalization.

vCyclin and vFLIP

vCyclin, which shares significant homology to cellular cyclin D2, complexes with CDK6 to phosphorylate and inhibit pRB and other cell cycle regulators. vFlip, encoded by a bicistronic mRNA species also encoding vCyclin, is a death effector domain (DED)-containing protein that interferes with apoptosis signaled through death receptors and stimulates the transcription factor, nuclear factor kappa B (NFkB).

Kaposin

Kaposin (or K12) is a small highly polymorphic protein that activates the mitogenic activated protein kinase (MAPK) signaling pathway. Genetic mutations leading to overactivation of MApK is a common theme in many human cancers, suggesting that Kaposin may play an analogous role in KS.

Although the latent genes are individually not transforming, endothelial cells immortalized by the SV40 Large T Ag (which mimics the inhibition of p53 by LANA-1 and -2) also stably expressing both vCyclin and vFlip formed small tumors in nude mice [9]. However, the full tumorigenic potential of this cell line was only realized in the presence of the paracrine secretions of a KSHV lytic gene, vGPCR, suggestive of a cooperative role for KSHV genes in Kaposi's sarcomagenesis.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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