Role for yeast inhibitor of apoptosis (IAP)-like proteins in cell division

Abstract

Inhibitors of apoptosis (IAPs) are a family of proteins that bear baculoviral IAP repeats (BIRs) and regulate apoptosis in vertebrates and Drosophila melanogaster. The yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe both encode a single IAP, designated BIR1 and bir1, respectively, each of which bears two BIRs. In rich medium, BIR1 mutant S. cerevisiae underwent normal vegetative growth and mitosis. Under starvation conditions, however, BIR1 mutant diploids formed spores inefficiently, instead undergoing pseudohyphal differentiation. Most spores that did form failed to survive beyond two divisions after germination. bir1 mutant S. pombe spores also died in the early divisions after spore germination and became blocked at the metaphase͞ anaphase transition because of an inability to elongate their mitotic spindle. Rather than inhibiting caspase-mediated cell death, yeast IAP proteins have roles in cell division and appear to act in a similar way to the IAPs from Caenorhabditis elegans and the mammalian IAP Survivin.Apoptosis is implemented by a mechanism highly conserved among metazoans. A number of mammalian cell death proteins resemble those from insects and nematodes both in structure and function, and some, such as members of the Bcl-2, caspase, and inhibitor of apoptosis (IAP) families are able to act in heterologous organisms (1), suggesting an ancient origin of the effector and control mechanisms of cell death.Although examples of cell-suicide mechanisms have been described in single-celled organisms (reviewed in ref.2), it is not yet known whether any similarity exists between the mechanisms of cell death in metazoans and unicellular organisms. In single-celled organisms, homologs of cell death molecules may be involved in cell death or may have unrelated roles. In either case, analysis of such proteins may reveal clues as to how they function. Although no homologs of Bcl-2 or caspases have been identified within single-celled organisms, by using low-stringency database searches we have identified homologs of IAP proteins in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe (3). We designated these genes BIR1 and bir1, respectively, because they bear a pair of BIR (baculovirus IAP repeat) motifs (4) within their amino termini.IAP proteins are a family of cell death inhibitors identified in baculoviruses, where they prevent defensive apoptosis of the host cell and thereby promote viral replication (5). Function of these baculoviral IAPs is conserved, because they also were able to inhibit apoptosis of mammalian cells (6), and most of the cellular homologs of IAPs identified in Drosophila and vertebrates are also cell death inhibitors (7-10). Nevertheless, it is possible that some IAPs have other functions, as at least one IAP from Caenorhabditis elegans is probably not involved in apoptosis but is required for cytokinesis during the first cell divisions after fertilization (11).Here we describe the phenotype of BIR1 and bir1 deletion mutants and localization of the prot...

Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras

“…Even a 2-h treatment of transformed 423DiR-1 cells with LY294002 and/or U0126 markedly diminished the localization of survivin to the mitotic spindle apparatus (data not shown). This suggests that, apart from direct or indirect transcriptional activation of survivin by c-H-Ras, other Ras-mediated effects on downstream targets are required to render survivin functional in its ancient role as protector of genome integrity (Li et al, 1998;Fraser et al, 1999;Uren et al, 1999Uren et al, , 2000. In this context, it appears interesting that the Raf/MEK/MAPK pathway is necessary also for the G2/M progression, where 40% of MAPKs was found associated with microtubuli (Hayne et al, 2000).…”

“…The contribution of survivin to cell division is evolutionary conserved. In yeast and C. elegans, proper chromosomal separation is strictly dependent on the action of proteins with survivin-like BIR domains (Uren et al, 1999;Fraser et al, 1999). These proteins in lower organisms, however, lack antiapoptotic activity, indicating that the survival function of the BIR-only containing proteins was superimposed by evolution.…”

The IAP family: endogenous caspase inhibitors with multiple biological activities

“…This cytokinesis defect could be partially suppressed by transgenic expression of survivin. In the yeast S. cerevisiae and S. probe there is only a single IAP protein, Bir1, which contains two BIRs [31]. This gene is required for spindle elongation and efficient meiotic division [31], indicating the cell cycle regulation function of IAP family proteins is evolutionarily conserved.…”

“…In the yeast S. cerevisiae and S. probe there is only a single IAP protein, Bir1, which contains two BIRs [31]. This gene is required for spindle elongation and efficient meiotic division [31], indicating the cell cycle regulation function of IAP family proteins is evolutionarily conserved. It is not clear at present whether the cell-cycle regulating activity of these BIR-containing proteins is related to their anti-apoptotic function.…”

Gene expression profiling of breast cells induced by X-rays and heavy ions

“…The present study indicated that BIRC2/CIAP1 induced changes in the apoptosis process. This gene belongs to a family of highly conserved anti-apoptotic proteins first identified in baculovirus and later in eukaryotic species from yeast to mammals (39,40). It has been reported that BIRC2/CIAP1 is an inhibitor of apoptosis and overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas (41).…”