Disease relevance of Nc

• In Drosophila, the caspase-9 counterpart Dronc is essential for most apoptotic death, whereas the caspase-8 homolog Dredd activates NF-kappaB signaling in response to gram-negative bacterial infection [1].
• These mutants present a range of defects, including extensive hyperplasia of hematopoietic tissues, supernumerary neuronal cells, and head involution failure. dronc genetically interacts with the Ced4/Apaf1 counterpart, Dark, and adult structures lacking dronc are disrupted for fine patterning [2].

High impact information on Nc

• These results indicate an apoptosis-independent role for DIAP1-mediated Dronc inhibition in Rac-mediated cell motility [3].
• This allows for local activation of the Dronc caspase, thereby preserving C4da neurons while severing their dendrites [4].
• Furthermore, orthologues of the apoptosome components, Ark (Apaf-1) and Dronc (caspase-9), are also required for the proper removal of bulk cytoplasm during spermatogenesis [5].
• However, unlike caspase activation in mammals, DRONC activation is not accompanied by the release of cytochrome c from mitochondria [6].
• Finally, we show that the dronc promoter has BR-C interaction sites, and that it can be transactivated by a specific isoform of BR-C [7].

Biological context of Nc

• The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis [8].
• Ectopic expression of DRONC induces cell death in Schizosaccharomyces pombe, mammalian fibroblasts and the developing Drosophila eye [9].
• We demonstrate that dronc gene expression is ablated or reduced in BR-C mutant flies [7].
• Using RNA interference in an ecdysone-responsive Drosophila cell line, we show that DRONC is essential for ecdysone-mediated cell death, and that dronc upregulation in these cells is controlled by BR-C [7].
• Recent data on DRONC also suggest that some fly caspases may have unique substrate specificities not ascribed to mammalian caspases [10].

Anatomical context of Nc

• In late third instar larvae, dronc mRNA is dramatically up-regulated in salivary glands and midgut before histolysis of these tissues [11].

Associations of Nc with chemical compounds

• These results suggest that DRONC is an effector of steroid-mediated apoptosis during insect metamorphosis [11].
• In both living and dying S2 cells, DIAP1 is cleaved by DRONC after glutamate residue Glu-205, located between the first and second BIR domains [12].
• DRONC prefers tetrapeptide substrates in which aliphatic amino acids are present at the P2 position, and the P1 residue can be either aspartate or glutamate [13].

Physical interactions of Nc

• This recognition is essential for DIAP1 binding to Dronc, and for targeting Dronc for ubiquitination [14].

Regulatory relationships of Nc

• Furthermore, we show that the RING finger of DIAP1 promotes the ubiquitination of both itself and of Dronc [8].
• In contrast to previous reports, we show that the dronc eye ablation phenotype can be suppressed by coexpression of the baculoviral caspase inhibitor p35 [15].
• The Drosophila Apaf-1 related killer (Dark) forms an apoptosome that activates Dronc, an apical procaspase in the intrinsic cell death pathway [16].

Other interactions of Nc

• DRONC, a key apical caspase in Drosophila, is the only known caspase that is transcriptionally regulated by ecdysone during development [7].
• Compensatory proliferation in Drosophila imaginal discs requires Dronc-dependent p53 activity [17].
• Dying midguts express the rpr, hid, ark, dronc, and crq cell death genes, suggesting that the core cell death machinery is involved in larval midgut cell death [18].
• A significant proportion of cellular DRONC and DRICE appears to localize near mitochondria, suggesting that an apoptosome may form in the vicinity of mitochondria in the absence of cytochrome c release [19].
• Dronc also interacts, both genetically and biochemically, with the CED-4/Apaf-1 fly homolog, Dark [15].

References