Showing papers by "Hermann Steller published in 2000"

Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function

Abstract: Induction of apoptosis in Drosophila requires the activity of three closely linked genes, reaper, hid and grim. Here we show that the proteins encoded by reaper, hid and grim activate cell death by inhibiting the anti-apoptotic activity of the Drosophila IAP1 (diap1) protein. In a genetic modifier screen, both loss-of-function and gain-of-function alleles in the endogenous diap1 gene were obtained, and the mutant proteins were functionally and biochemically characterized. Gain-of-function mutations in diap1 strongly suppressed reaper-, hid- and grim-induced apoptosis. Sequence analysis of these alleles revealed that they were caused by single amino acid changes in the baculovirus IAP repeat domains of diap1, a domain implicated in binding REAPER, HID and GRIM. Significantly, the corresponding mutant DIAP1 proteins displayed greatly reduced binding of REAPER, HID and GRIM, indicating that REAPER, HID and GRIM kill by forming a complex with DIAP1. These data provide strong in vivo evidence for a previously published model of cell death regulation in Drosophila.

A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.

Abstract: Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-β signalling pathway) ARTS is expressed in many cells and acts to enhance cell death induced by TGF-β or, to a lesser extent, by other apoptotic agents Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis

Biochemical and genetic interactions between Drosophila caspases and the proapoptotic genes rpr, hid, and grim.

Abstract: In Drosophila melanogaster, the induction of apoptosis requires three closely linked genes, reaper (rpr), head involution defective (hid), and grim. The products of these genes induce apoptosis by activating a caspase pathway. Two very similar Drosophila caspases, DCP-1 and drICE, have been previously identified. We now show that DCP-1 has a substrate specificity that is remarkably similar to those of human caspase 3 and Caenorhabditis elegans CED-3, suggesting that DCP-1 is a death effector caspase. drICE and DCP-1 have similar yet different enzymatic specificities. Although expression of either in cultured cells induces apoptosis, neither protein was able to induce DNA fragmentation in Drosophila SL2 cells. Ectopic expression of a truncated form of dcp-1 (DeltaN-dcp-1) in the developing Drosophila retina under an eye-specific promoter resulted in a small and rough eye phenotype, whereas expression of the full-length dcp-1 (fl-dcp-1) had little effect. On the other hand, expression of either full-length drICE (fl-drICE) or truncated drICE (DeltaN-drICE) in the retina showed no obvious eye phenotype. Although active DCP-1 protein cleaves full-length DCP-1 and full-length drICE in vitro, GMR-DeltaN-dcp-1 did not enhance the eye phenotype of GMR-fl-dcp-1 or GMR-fl-drICE flies. Significantly, GMR-rpr and GMR-grim, but not GMR-hid, dramatically enhanced the eye phenotype of GMR-fl-dcp-1 flies. These results indicate that Reaper and Grim, but not HID, can activate DCP-1 in vivo.

A comparison of programmed cell death between species.

Abstract: Key components of the programmed cell death pathway are conserved between Caenorhabditis elegans, Drosophila melanogaster and humans. The search for additional homologs has been facilitated by the availability of the entire genomic sequence for each of these organisms.

Drosophila p53: meeting the Grim Reaper.

Abstract: The recent discovery of a Drosophila orthologue of the p53 tumour suppressor promises new insights into the complex function, regulation and evolution of one of the most intensely studied human disease proteins.

Compositions and methods for the screening of compounds to enhance or reduce apoptosis

Abstract: Nucleotide acid sequences and corresponding translated products of novel mutant forms of the Drosophila DIAP1 gene are described. Such sequences and products are useful in screening methods for identifying and testing agonists and antagonists of DIAP1.