TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer

Caspase-associated recruitment domains (CARDs) are protein interaction doma ins that participate in activation or suppression of CARD-carrying members of the caspase family of apoptosis-inducing proteases. A novel CARD-contain ing protein was identified that is overexpressed in some types of cancer an d that binds and suppresses activation of procaspase-9, which we term TUCAN (tumor-upregulated CARD-containing antagonist of caspase nine). The CARD d omain of TUCAN selectively binds itself and procaspase-9. TUCAN interferes with binding of Apaf1 to procaspase-9 and suppresses caspase activation ind uced by the Apaf1 activator, cytochrome c. Overexpression of TUCAN in cells by stable or transient transfection inhibits apoptosis and caspase activat ion induced by Apaf1/ caspase-9-dependent stimuli, including Bax, VP16, and staurosporine, but not by Apafl/caspase-9-independent stimuli, Fas and gra nzyme B. High levels of endogenous TUCAN protein were detected in several t umor cell lines and in colon cancer specimens, correlating with shorter pat ient survival. Thus, TUCAN represents a new member of the CARD family that selectively suppresses apoptosis induced via the mitochondrial pathway for caspase activation.