The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc.
The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) protein is functionally pleiotropic. LANA contributes to KSHV-associated pathogenesis, in part, by increasing entry of cells into S phase through a process that is driven by LANA interaction with the serine-threonine kinase glycogen synthase kinase 3 (GSK-3) and stabilization of beta-catenin. We now show that LANA affects the activity of another protein involved in cell cycle regulation, c-Myc. Sequencing of c-Myc coding sequences revealed that c-Myc in KSHV-positive primary effusion lymphoma (PEL) cell lines is wild type in the N-terminal region that regulates c-Myc protein stability. Despite this, c-Myc in PEL cells is stabilized. In LANA-expressing cells, inactivation of nuclear GSK-3 reduced phosphorylation of c-Myc at Thr58 and contributed to c-Myc stabilization by decreasing c-Myc ubiquitination. Phosphorylation of c-Myc on Ser62 also affects c-Myc stability and function. We now show that LANA increases the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) and increases ERK phosphorylation of c-Myc on Ser62. LANA also interacted with c-Myc, and c-Myc amino acids 147 to 220 were required for this interaction. LANA (L1006P) retained the ability to bind to c-Myc and activate ERK1, indicating that these events did not require LANA interaction with GSK-3. Thus, LANA stabilizes c-Myc; prevents the phosphorylation of c-Myc at Thr58, an event that promotes Myc-induced apoptosis; and independently stimulates phosphorylation of c-Myc at Ser62, an event that transcriptionally activates c-Myc. LANA-mediated manipulation of c-Myc function is likely to contribute to KSHV-associated tumorigenesis through the induction of c-Myc regulated cellular genes, as well as by the stimulation of cell cycle progression.
Liu
Jianyong
J
Viral Oncology Program, Sidney Kimmel Cancer Center, and Department of Pharmacology, Johns Hopkins School of Medicine, Bunting-Blaustein Bldg., CRB308, 1650 Orleans St., Baltimore, MD 21231, USA.
Martin
Heather J
HJ
Liao
Gangling
G
Hayward
S Diane
SD
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000378:metabolism*; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000956:Antigens, Viral; C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D025801:Ubiquitin; C109540:latency-associated nuclear antigen; D013912:Threonine; D012694:Serine; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3