Title | Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Bubman D, Guasparri I, Cesarman E |
Journal | Oncogene |
Volume | 26 |
Issue | 34 |
Pagination | 4979-86 |
Date Published | 2007 Jul 26 |
ISSN | 0950-9232 |
Keywords | Antigens, Viral, B-Lymphocytes, Cell Line, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Lymphoma, Non-Hodgkin, Nuclear Proteins, Proto-Oncogene Proteins c-myc, RNA Interference, Threonine |
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-3beta (GSK-3beta). 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-3beta-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3beta-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells. |
DOI | 10.1038/sj.onc.1210299 |
Alternate Journal | Oncogene |
PubMed ID | 17310999 |
Grant List | R01 CA068939 / CA / NCI NIH HHS / United States |
Related Faculty:
Ethel Cesarman, M.D., Ph.D.