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Journal of Virology, October 2007, p. 10451-10459, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00804-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Kaposi's Sarcoma-Associated Herpesvirus LANA Protein Stabilizes and Activates c-Myc{triangledown}

Jianyong Liu,1 Heather J. Martin,1,2 Gangling Liao,1 and S. Diane Hayward1,2*

Viral Oncology Program, Sidney Kimmel Cancer Center,1 Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, Maryland 212312

Received 13 April 2007/ Accepted 9 July 2007

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 ß-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.

* Corresponding author. Mailing address: Department of Oncology, Johns Hopkins School of Medicine, Bunting-Blaustein Bldg., CRB308, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 614-0592. Fax: (410) 502-6802. E-mail: dhayward{at}jhmi.edu

{triangledown} Published ahead of print on 18 July 2007.

Journal of Virology, October 2007, p. 10451-10459, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00804-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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