Survivin and the IAPs

965 Survivin is a bifunctional protein that suppresses apoptosis and regulates cell division (1). This protein has garnered great interest as a potential drug target because its expression is among the most tumor-specific of all human gene products (2). While fetal tissues contain abundant Survivin mRNA and protein, most normal adult tissues do not. In contrast, the vast majority of tumors express Survivin protein at high levels, suggesting that reactivation of SURVIVIN gene expression occurs commonly in cancers (3). The mechanisms by which Survivin regulates cell death and cell division are highly controversial. Indeed, even the premise that Survivin regulates apoptosis has been challenged, primarily on the grounds that Survivin homologues in yeast and Caenorhabditis elegans operate as regulators of cell division but not cell survival (reviewed in refs. 4, 5). Heretofore, the preponderance of evidence that mammalian Survivin suppresses apoptosis was based on overexpression of the protein in cultured cell lines. The absence of in vivo data on this point has now been remedied with a paper in this issue of the JCI by Altieri and colleagues (6). In an accompanying paper (7), the same investigators show how emerging knowledge about Survivin regulation might be use to develop a new gene therapy strategy for cancer. Seeking to model events in tumors, Grossman et al. (6) placed the Survivin cDNA under the control of the keratin 14 (K14) promoter and generated transgenic mice that produce Survivin constitutively in epidermal keratinocytes. The skin is an easily accessible tissue that displays the full gamut of events relevant to tumorigenesis, including cell proliferation, differentiation, and death. Betting persons might have placed their wagers on seeing a defect in cell division or differentiation in K14-Survivin mice, but such was not the case. Instead, the keratinocytes of these Survivin-overexpressing mice demonstrated resistance to apoptosis, thus providing the first evidence that Survivin can suppress cell death in vivo. Specifically, overexpression of Survivin significantly reduced the numbers of apoptotic cells generated in the epidermis following exposure to ultraviolet-B (UVB) radiation (sunburn). While these data do not go as far as to establish a role for Survivin in homeostatic programmed cell death, they do at least indicate that the overexpression of Survivin (which is seen in many tumors) can result in an antiapoptotic state in vivo.