Mechanism for elimination of a tumor suppressor: Aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma

Loss of tumor suppressors that restrain important oncoproteins such as c-My c may contribute to malignant progression. Bin1 is an adapter protein with features of a tumor suppressor that was identified through its interaction with and inhibition of the oncogenic properties of c-Myc, In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanom a cells at different stages of tumor progression, Evidence is provided that Bin1 function is abrogated in melanoma cells by a mechanism based on aberr ant splicing of a tissue-specific exon, Specifically, most melanoma cells i nappropriately expressed exon 12A, which is spliced alternately into Bin1 i soforms found in brain but not into isoforms found in melanocytes and many other nonneuronal cells. Exon 12A sequences abolished the ability of Bin1 t o inhibit malignant transformation by c-Myc or adenovirus E1A. Similarly, t hese sequences abolished the ability of Bin1 to induce programmed cell deat h in melanoma cells that endogenously expressed exon 12A. Our findings sugg est that aberrant splicing of Bin1 may contribute to melanoma progression, and they define a mechanism by which the activity of a tumor suppressor can be eliminated in cells.