SCFSkp2 complex targeted by Epstein-Barr virus essential nuclear antigen.

Abstract	The stability of cell cycle checkpoint and regulatory proteins is controlled by the ubiquitin-proteasome degradation machinery. A critical regulator of cell cycle molecules is the E3 ubiquitin ligase SCFSkp2, known to facilitate the polyubiquitination and degradation of p27, E2F, and c-myc. SCFSkp2 is frequently deregulated in human cancers. In this study, we have revealed a novel link between the essential Epstein-Barr virus (EBV) nuclear antigen EBNA3C and the SCFSkp2 complex, providing a mechanism for cell cycle regulation by EBV. EBNA3C associates with cyclin A/cdk2 complexes, disrupting the kinase inhibitor p27 and enhancing kinase activity. The recruitment of SCFSkp2 activity to cyclin A complexes by EBNA3C results in ubiquitination and SCFSkp2-dependent degradation of p27. This is the first report of a viral protein usurping the function of the SCFSkp2 cell cycle regulatory machinery to regulate p27 stability, establishing the foundation for a mechanism by which EBV regulates cyclin/cdk activity in human cancers.
Authors	Jason S Knight, Nikhil Sharma, Erle S Robertson
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 25 Issue 5 Pg. 1749-63 (Mar 2005) ISSN: 0270-7306 [Print] United States
PMID	15713632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Antigens, Viral Carrier Proteins Cell Cycle Proteins Cyclin A EBNA-3C, epstein-barr virus Epstein-Barr Virus Nuclear Antigens RBX1 protein, human S-Phase Kinase-Associated Proteins Tumor Suppressor Proteins Ubiquitins Cyclin-Dependent Kinase Inhibitor p27 Ubiquitin-Protein Ligases Proteasome Endopeptidase Complex
Topics	Antigens, Viral (genetics, metabolism) Carrier Proteins (physiology) Cell Cycle (physiology) Cell Cycle Proteins (metabolism) Cell Line, Tumor Cyclin A (metabolism) Cyclin-Dependent Kinase Inhibitor p27 Epstein-Barr Virus Nuclear Antigens (genetics, metabolism) Herpesvirus 4, Human (physiology) Humans Immunoprecipitation Neoplasms (metabolism) Proteasome Endopeptidase Complex (physiology) S-Phase Kinase-Associated Proteins (metabolism) Transfection Tumor Suppressor Proteins (metabolism) Ubiquitin-Protein Ligases (physiology) Ubiquitins (metabolism)

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