Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen.
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.
Bubman
D
D
Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
Guasparri
I
I
Cesarman
E
E
D000956:Antigens, Viral / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000821:virology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013912:Threonine / Q000378:metabolism
D000956:Antigens, Viral; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C109540:latency-associated nuclear antigen; D013912:Threonine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3