MAGE-A4 Interacts with the Liver Oncoprotein Gankyrin and Suppresses Its Tumorigenic Activity

Toshikazu Nagao, Hiroaki Higashitsuji, Kohsuke Nonoguchi, Toshiharu Sakurai, Simon Dawson, R. John Mayer, Katsuhiko Itoh, Jun Fujita
2003 Journal of Biological Chemistry  
Hepatocellular carcinoma ranks among the most common malignancies in Southeast Asia and South Africa. Although there are many modalities of treatment, the recurrence and metastasis rates are high, and the prognosis is unsatisfactory. Gankyrin, a recently found oncoprotein, is a promising target for drug therapy because it is overexpressed in all studied hepatocellular carcinomas. Gankyrin contains six ankyrin repeats and interacts with Rb, Cdk4, and the S6 ATPase of the 26 S proteasome. In this
more » ... proteasome. In this study, a yeast two-hybrid screen with gankyrin has identified MAGE-A4 as another interacting protein. The interaction, mediated by the C-terminal half of MAGE-A4, was reproduced in mammalian cells. The interaction was specific to MAGE-A4, because other MAGE family proteins structurally similar to MAGE-A4, i.e. MAGE-A1, MAGE-A2, and MAGE-A12, did not bind to gankyrin. MAGE-A4 partially suppressed both anchorage-independent growth in vitro and tumor formation in athymic mice of gankyrin-overexpressing cells. The ability of mutant MAGE-A4 to interact with gankyrin correlated with the ability to suppress the anchorage-independent growth. These results demonstrate that MAGE-A4 binds to gankyrin and suppresses its oncogenic activity. So far, the major focus of studies on the MAGE proteins has been on their potential for cancer immunotherapy. Our results may also shed light on novel functions for MAGE-A proteins. Gankyrin (gann ankyrin repeat protein, also known as PSMD10 and p28) is an oncoprotein, the expression of which is increased (1, 2) in hepatocellular carcinomas (HCCs). 1 Gankyrin consists of six ankyrin repeats and a 38-amino acid N-terminal extension and binds to the retinoblastoma tumor suppressor protein (Rb), the S6 ATPase subunit of the 26 S proteasome (PSMC4, RPT3, TBP7), and cyclin-dependent kinase 4 (Cdk4) (1, 3, 4) . Overexpression of gankyrin increases
doi:10.1074/jbc.m206104200 pmid:12525503 fatcat:abjxufruqbambftbajinyedqpa