A novel viral mechanism for dysregulation of beta-catenin in Kaposi's sarcoma-associated herpesvirus latency.
The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) is expressed in all KSHV-associated tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). We found that beta-catenin is overexpressed in both PEL cells and KS tissue. Introduction of anti-LANA small interfering RNA (siRNA) into PEL cells eliminated beta-catenin accumulation; LANA itself upregulated expression of beta-catenin in transfected cells. LANA stabilizes beta-catenin by binding to the negative regulator GSK-3beta, causing a cell cycle-dependent nuclear accumulation of GSK-3beta. The LANA C terminus contains sequences similar to the GSK-3beta-binding domain of Axin. Disruption of this region resulted in a mutant LANA that failed to re-localize GSK-3beta or stabilize beta-catenin. The importance of this pathway to KSHV-driven cell proliferation was highlighted by the observation that LANA, but not mutant LANA, stimulates entry into S phase. Redistribution of GSK-3beta can therefore be a source of beta-catenin dysregulation in human cancers.
Fujimuro
Masahiro
M
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Wu
Frederick Y
FY
ApRhys
Colette
C
Kajumbula
Henry
H
Young
David B
DB
Hayward
Gary S
GS
Hayward
S Diane
SD
D000595:Amino Acid Sequence; D000956:Antigens, Viral; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003513:Cycloheximide / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering; D016415:Sequence Alignment; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D017735:Virus Latency; D051176:beta Catenin
D000956:Antigens, Viral; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051176:beta Catenin; C109540:latency-associated nuclear antigen; D019938:Cyclin D1; D003513:Cycloheximide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3