A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma–associated herpesvirus latency

Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that beta-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated beta-catenin accumulation; LANA itself upregulated expression of beta-catenin in transfected cells. LANA stabilizes beta-catenin by binding to the negative regulator GSK-3beta, causing a cell cycle-dependent nuclear accumulation of GSK-3beta. The LANA C terminus contains sequences similar to the GSK-3beta-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3beta or stabilize beta-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3beta can therefore be a source of beta-catenin dysregulation in human cancers.

Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

“…An interaction between GSK-3b and LANA in PELs was previously reported (Fujimuro et al, 2003). GSK-3b was also shown to interact directly with c-Myc both in vitro and in transfected COS-7 cells (Gregory et al, 2003).…”

“…Fujimuro et al (2003) found that LANA can induce cell-cycle-dependent nuclear localization of GSK-3b, thereby limiting its activity in the cytoplasm. In addition, most of the nuclear kinase is in an inactive Ser 9 -phosphorylated form while bound to LANA (Hayward et al, 2006).…”

“…From these experiments we concluded that KSHV-infected PEL cell lines have an abnormally stable c-Myc protein. (Fujimuro et al, 2003), which is a known c-Myc transcriptional activator in non-transformed cells (Cadigan and Nusse, 1997;Polakis, 2000). Therefore, the viral protein could enhance c-Myc transcription.…”

“…c-Myc is underphosphorylated on T58 in PELs LANA can inhibit GSK-3b in PEL cells and change its cellular localization from cytoplasmic to nuclear, with the most noticeable effect in the S phase of the cell cycle (Fujimuro et al, 2003). As GSK-3b is known to be the c-Myc T58 kinase in vivo (Gregory et al, 2003), its inhibition should lead to a reduction in c-Myc phosphorylation on this residue.…”

“…In addition, LANA associates with various proteins including p53 and pRb and through these interactions stimulates pathways involved in survival and proliferation (Friborg et al, 1999;Radkov et al, 2000). Recently, it was found that LANA promotes stabilization of b-catenin in PEL cells by inhibiting its negative regulator, GSK-3b (Fujimuro et al, 2003). GSK-3b phosphorylates numerous substrates, including more than a dozen transcription factors, such as activator protein-1 (AP-1), cAMP response element binding protein (CREB), nuclear factor of activated T cells (NFAT) and c-Myc (Jope and Johnson, 2004).…”