1B). The authors deduct from this finding that increased proliferation is a consequence of increased apoptosis. However, the direct link between these two separate cellular fates is not entirely clear. It is known that some primarily apoptotic proteins including caspases or FADD (Fas-associated protein with death domain) exert nonapoptotic functions like cellular activation, proliferation, and differentiation (reviewed in Lamkanfi et al.6 and Strasser et al.7). However, the findings are somewhat contradictory, especially in the liver. The detailed understanding of nonapoptotic functions of caspases Fulvestrant purchase (or FADD) including the precise mechanisms, upstream

activators, and downstream targets will tremendously help cell death researchers and potentially foster future antineoplastic drug development Decitabine manufacturer (reviewed in Strasser et al.7). Another possible explanation of how increased apoptosis translates into carcinogenesis might be found in the up-regulation of Survivin, an inhibitor of apoptosis (IAP) family member that the authors found to be up-regulated

in hepatocytes lacking Mcl-1 (see figure 2, C and D, in Weber et al.1). Survivin is involved in cell cycle progression, proliferation, assembly of the mitotic spindle, but also apoptosis (reviewed in Altieri8). Survivin is highly expressed in a multitude of cancers, independently of their mitotic index, indicating that it is an interesting candidate to drive cell division and cell cycle entry. Its expression, however, might be a consequence (or unrelated effect) of increased proliferation rather than its cause. The study by Weber et al. would benefit from functional data on the role of Survivin; however, genetically accurate testing involves breeding Survivin-deficient mice into the Mcl-1fl/fl–AlbCre background. Defining the key players that drive proliferation in Mcl-1–deficient hepatocytes constitutes an intriguing and difficult task ahead. Solving the key components of potential caspase-mediated

proliferation will offer a variety of new insights into liver homeostasis and probably other tissues as well. What is the apoptotic stimulus that kills Oxalosuccinic acid Mcl-1–deficient hepatocytes in unchallenged mice? The mitochondrial permeabilization by active Bak or Bcl-2–associated X protein (Bax) within hepatocytes is critical for intrinsic cell death progression. Although it is not clear which prosurvival Bcl-2 family members exactly neutralize Bax, its homologue Bak is subject to negative regulation specifically by Mcl-1 and Bcl-x(L) but not other prosurvival family members.9 Mcl-1 guards Bak and shields the outer mitochondrial membrane from apoptotic stimuli transmitted by BH3-only proteins such as Bim, Puma, and Noxa (Fig. 1A). The report by Weber et al. presents data on apoptosis (together with data from Vick et al.2) but does not provide evidence on the upstream stimuli that induce cell death.