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

Abstract

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's lymphoma, which is associated with infection by Kaposi's sarcoma herpesvirus (KSHV)/human herpesvirus-8. The c-Myc transcription factor plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression owing to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-myc oncogene in PEL. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PEL. We report that PEL cells have abnormally stable c-Myc protein. The turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, including phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase kinase-3b (GSK-3b). Our data show that the impaired c-Myc degradation in PEL cells is associated with a significant underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in human embryonic kidney 293 or peripheral blood B cells leads to post-transcriptional deregulation of c-Myc protein. Conversely, when LANA is eliminated from PEL cells using RNA interference, GSK-3b-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3b-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells.

Stimulation of c-Myc Transcriptional Activity by vIRF-3 of Kaposi Sarcoma-associated Herpesvirus

“…Additional experiments are needed to determine whether the association of vIRF-3 with c-Myc can also alter the DNA-binding specificity of c-Myc, which may result in the activation of a distinct set of genes that are not regulated by c-Myc alone. Recently, two groups linked another KSHV-encoded latent gene, LANA, to impaired c-Myc degradation in PEL cells (59,60). They showed that LANA stabilizes c-Myc protein by preventing its phosphorylation on threonine 58 and simultaneously stimulates its phosphorylation at serine 62, which leads to c-Myc transcriptional activation.…”

Viral epigenomes in human tumorigenesis

“…All of them are linked to viral maintenance and to the perturbation of the host immune response (Dourmishev et al, 2003;zur Hausen, 2006;Areste´and Blackbourn, 2009). In particular, several of these proteins (LANA, v-cyclinD, vFLIP and kaposin) can affect the main tumorigenic pathways involved in regulating important tumor suppressors and oncogenic genes in mammals (Godden-Kent et al, 1997;Friborg et al, 1999;Radkov et al, 2000;Fujimuro et al, 2003;Guasparri et al, 2004;McCormick and Ganem, 2005;Bubman et al, 2007;Di Bartolo et al, 2008).…”

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

“…Unlike other lymphomas, no signature translocation or single gene mutation has been associated with PEL to date. The p53 tumor suppressor protein appears functional in PEL cell lines, 15 the Myc locus un-rearranged, although the protein is unusually stable, 16 and no amplifications or deletions are reported for Bcl-2, 2 Bcl-6, 17 Ras, 2 the catalytic subunit of PI3K, 18 phosphatase with tensin homolog or p16/INK4. 18 We therefore used the Affymetrix 6.0 single nucleotide polymorphism (SNP)-based microarray to conduct comparative genomic hybridization (CGH) to look at the global genomic profile of PEL cells.…”