BIR-1, a C. elegans BIRP, is probably not involved in the general regulation of apoptosis but is required for embryonic cytokinesis. We suggest that BIRPs may regulate cytoskeletal changes in diverse biological processes including cytokinesis and apoptosis.

Apoptosis as a form of programmed cell death (PCD) in multicellular organisms is a well-established genetically controlled process that leads to elimination of unnecessary or damaged cells. Recently, PCD has also been described for unicellular organisms as a process for the socially advantageous regulation of cell survival. The human Bcl-2 family member Bak induces apoptosis in mammalian cells which is counteracted by the Bcl-x L protein. We show that Bak also kills the unicellular fission yeast Schizosaccharomyces pombe and that this is inhibited by coexpression of human Bcl-x L . Moreover, the same critical BH3 domain of Bak that is required for induction of apoptosis in mammalian cells is also required for inducing death in yeast. This suggests that Bak kills mammalian and yeast cells by similar mechanisms. The phenotype of the Bak-induced death in yeast involves condensation and fragmentation of the chromatin as well as dissolution of the nuclear envelope, all of which are features of mammalian apoptosis. These data suggest that the evolutionarily conserved metazoan PCD pathway is also present in unicellular yeast.Programmed cell death (PCD) in metazoans is an essential homeostatic mechanism permitting the removal of surplus cells during morphogenesis and tissue maintenance and the deletion of cells that present a risk to the organism because they are mutated or infected (10,19,35,36,40). For vertebrates, the descriptive name commonly given to the process of PCD is apoptosis. Classical apoptosis is characterized by membrane blebbing, cell shrinkage, chromatin condensation, and nuclear and cellular fragmentation, and it results from the activation of an intrinsic suicide program (47). Recent studies implicate the dysregulation of PCD in the pathophysiology of several human diseases, including AIDS (12, 28), neurodegenerative disease (25,37,44), and cancer (for a review, see reference 42).The basal machinery responsible for metazoan PCD is highly evolutionarily conserved and, at its execution level, involves the action of a discrete class of cysteine proteases, of which the prototypes are the interleukin-1␤-converting enzyme in humans and Ced-3 in the nematode (49). Also conserved are key regulators of apoptosis: in Caenorhabditis elegans the Ced-9 protein and in humans the Bcl-2 protein family (18, 46), which comprises both suppressors (e.g., Bcl-2 and Bcl-x L ) and promoters (e.g., Bax and Bak) of PCD (17,30,46).Recently, there have been several reports describing apparent PCD in the unicellular eukaryotes Tetrahymena thermophila, Dictyostelium discoideum, Trypanosoma brucei rhodsiense, and Trypanosoma cruzi and even in bacteria (2, 6, 45, 48; for an overview, see reference 1). PCD in unicellular organisms might facilitate constant selection for the fittest cell in the colony or optimal adaptation of cell numbers to the environment or might serve as a means for altruistic cell death to prevent the spread of virus in the event of infection.It has been shown that expression of the mammalian Bax protein in th...

Using S. pombe as a model system in which to assay CED-4 function, we have identified a potential direct role for CED-4 in chromatin condensation. Chromatin condensation is a ubiquitous feature of metazoan apoptosis that has yet to be linked to an effector. The CED-9-mediated rescue of CED-4-induced lethality in this system and the interaction of the two proteins in the yeast two-hybrid analysis suggest that CED-9 inhibits CED-4 action by direct physical association.

No abstract

Apoptosis of mammalian cell is under the control of a wide range of intracellular and extracellular factors-amongst them proteases, protein kinases, cytokines and the protein products of oncogenes and tumour suppressor genes. The c-myc proto-oncogene encodes an essential component of the cell's proliferative machinery and its deregulated expression is implicated in many cancers. Under certain conditions, c-Myc also acts as a potent inducer of apoptosis. We have developed a 'switchable' chimaeric c-Myc protein whose activity is dependent on the synthetic ligand, 4-hydroxytamoxifen. In cells expressing this switchable c-Myc, proliferation and apoptosis in cultured fibroblasts can be regulated by addition of 4-hydroxytamoxifen. We have further demonstrated the utility of a switchable gene transcription system for the induction of proteins with pro-apoptotic effect. Myc-induced apoptosis is inhibited by the action of certain cytokines or by expresson of exogenous proteins with anti-apoptotic potential such as Bcl-2. We show that inhibition of p53 using dominant negative molecules inhibits apoptosis induced by DNA damage but has little effect on Myc-induced apoptosis. Finally, we have also been able to modulate a relatively late stage in apoptosis using inhibitors of cysteine proteases. Our data suggest a model in which the integrated activities of several proteins with diverse molecular functions may determine whether a particular cell undergoes apoptosis but that, once the actual catalytic machinery is engaged, the apoptotic process is irreversible.