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Identification of AF17 As a Downstream Gene of the ß-catenin/T-Cell Factor Pathway and Its Involvement in Colorectal Carcinogenesis¹

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [Y-M. L., K. O., S. S., H. I., M. F., N. M., Y. N., Y. F.]; SNP Research Center, Riken (Institute of Physical and Chemical Research), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [T. Ta., T. Ts.]; and Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan [Y-M. L., K-C. Y.]

To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to isolate genes involved in the ß-catenin/T-cell factor pathway. In the experiments reported here, analysis by cDNA microarray indicated that AF17, a fusion partner of the MLL gene in acute leukemias with t(11;17)(q23;q21), was transactivated according to accumulation of ß-catenin. Expression of AF17 was significantly enhanced in 8 of the 12 colorectal cancer tissues examined. Introduction of a plasmid designed to express AF17 stimulated growth of NIH3T3 cells, and fluorescence-activated cell sorter analysis indicated that the AF17 regulation of cell-cycle progression was occurring mainly at the G₂-M transition. Our results suggest that the AF17 gene product is likely to be involved in the ß-catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein. These findings should aid development of new strategies for diagnosis, treatment, and prevention of colon cancers and acute leukemias by clarifying the pathogenesis of these conditions.

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