BIOLOGICAL OVERVIEW

Death caspase-1 (Dcp-1) is the first known Drosophila member of the caspase family of ICE/CED-3 proteases thought to play a role in apoptosis or programmed cell death. ICE was originally described as the cysteine protease required for cleavage of pro-interleukin-1ß in order to generate the active cytokine. CED-3 is a C. elegans cell death gene, with homology to mammalian ICE (Yuan, 1993). The term caspase is based on two catalytic properties of these enzymes. The "c" refers to a cysteine protease mechanism, and "aspase" refers to the group's ability to cleave aspartic acid, the most distinctive catalytic feature of this protease family. Each of these enzymes is synthesized as a proenzyme, proteolytically activated to form a heterodimeric catalytic domain. To date, ten homologs in humans have been discovered (Alnemri, 1996).

Three apoptotic activators (Reaper, Wrinkled/Head involution defective and Grim) have been identified in Drosophila. All three possess death domains, identifying them as proteins that act as mediators between different signaling pathways and the cell death program. The products of these genes appear to activate one or more caspases, because cell killing by Reaper, HID and Grim is blocked by the baculovirus protein p35, a specific inhibitor of caspases (Song, 1997 and references).

Dcp-1 is also capable of inducing cell death. The gene was expressed in several mammalian cell lines. Cells expressing Dcp-1 display the typical apoptotic morphology, such as condensed, rounded cell morphology and severe membrane blebing. A cell-free apoptosis system was used to investigate apoptosis-like nuclear events. In this system, Dcp-1 treatment results in fragmentation of chromosomal DNA that displays the characteristic apoptotic DNA ladder. It appears that Dcp-1 is able to engage at least part of the apoptotic program in mammalian cells (Song, 1997).

No significant abnormalities in the pattern of cell death are seen in dcp-1 mutants. Either there is sufficient Dcp-1 protein encoded maternally, or there are additional caspases performing a redundent function. However, dcp-1 mutation causes lethality during larval stages. Although most of the dcp-1 mutants die before the third instar larval stage, some reach that stage and display several abnormalities. Mutant larvae lack imaginal discs and gonads. In addition, they have fragile trachea. However, the most prominent phenotype found in these larvae is the presence of melanotic tumors located in various parts of the body. Melanotic tumors can result from either the overproliferation of blood cells or from an immune response toward abnormal cells and tissues in the larva. In dcp-1 mutants, there is no evidence for hyperplasia of the lymph glands or overproliferation of blood cells. This suggests an immune reaction toward abnormal tissues or cells, possible resulting from a defect in the ability to carry out cell death (Song, 1997).

The cytoplasmic region of Fas, a mammalian death factor receptor, shares a limited homology with Reaper, an apoptosis-inducing protein in Drosophila. Expression in Drosophila cells of either the Fas cytoplasmic region (FasC) or reaper causes cell death. The death process induced by FasC or reaper is inhibited by crmA or p35, suggesting that in both cases the death process is mediated by caspase-like proteases. Both Ac-YVAD aldehyde and Ac-DEVD aldehyde, specific inhibitors of caspase 1- and caspase 3-like proteases, respectively, inhibited the FasC-induced death of Drosophila cells. However, the cell death induced by Reaper is inhibited by Ac-DEVD aldehyde, but not by Ac-YVAD aldehyde. A caspase 1-like protease activity that preferentially recognizes the YVAD sequence gradually increases in the cytosolic fraction of the FasC-activated cells, whereas the caspase 3-like protease activity recognizing the DEVD sequence is observed in the Reaper-activated cells. Partial purification and biochemical characterization of the proteases indicates that there are at least three distinct caspase-like proteases in Drosophila cells that are differentially activated by FasC and Reaper. The conservation of the Fas-death signaling pathway in Drosophila cells, which is distinct from that for Reaper, may indicate that cell death in Drosophila is controlled not only by the Reaper suicide gene, but also by a Fas-like killer gene (Kondo, 1997a).

PROTEIN STRUCTURE

Amino Acids - 323

Structural Domains

Caspases are synthesized as inactive proenzymes that are proteolytically processed to form the active heterodimer consisting of a 10 kD and 20 kD subunit. The consensus sequence regulating this cleavage is found in the expected region of Dcp-1. The prodomain is only 33 amino acids (Song, 1997).

date revised: 15 December 97 

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