Disease relevance of W

• Amsacta moorei Entomopoxvirus inhibitor of apoptosis suppresses cell death by binding Grim and Hid [1].
• This inhibition is overcome by several apoptosis stimulators, including Drosophila Hid and mammalian Smac/DIABLO, which bind to 65-residue baculovirus IAP repeat (BIR) domains found in one to three copies in all IAPs [2].

High impact information on W

• Decreased activity of this pathway enhances, and increased activity suppresses, apoptosis induced by ectopic expression of the cell death regulators reaper (rpr) and head involution defective (hid) [3].
• By using transgenic animals and cultured cells, we show that MAPK phosphorylation sites in Hid are critical for this response [4].
• The head involution defective gene of Drosophila melanogaster functions in programmed cell death [5].
• Here we report the isolation of a second gene in this region, head involution defective (hid), which plays a similar role in PCD. hid mutant embryos have decreased levels of cell death and contain extra cells in the head [5].
• We show that Rpr, but not Hid (head involution defective), promotes significant DIAP1 degradation [6].

Biological context of W

• Conversely, cell death induced by overexpression of Hid was suppressed by gain-of-function mutations of the genes coding for MEK and ERK [7].
• A second Drosophila IAP, DIAP2, also binds Rpr and Hid and inhibits apoptosis in multiple contexts when overexpressed [8].
• Increasing the genetic dose of diap2 results in an increased immune response, whereas expression of Rpr or Hid results in down-regulation of DIAP2 protein levels [8].
• Although the abnormal wing phenotype caused by the Wrinkled (W) mutation is quite different from the one resulting from the loss-of-function hid mutations, the characterization of EMS-induced W revertants reveals that W is actually an antimorphic allele of hid [9].
• Molecular genetic studies in Drosophila have revealed the existence of three novel apoptotic activators, reaper, head involution defective and grim [10].

Anatomical context of W

• We show here that ecdysone-induced expression of the death activator genes reaper (rpr) and head involution defective (hid) is required for destruction of the larval midgut and salivary glands during metamorphosis, with hid playing a primary role in the salivary glands and rpr and hid acting in a redundant manner in the midguts [11].
• Furthermore, a peptide representing the amino terminus of Hid was sufficient to activate caspases in cytosolic extract, and this activity was not enhanced by addition of mitochondria or mitochondrial lysate [12].
• Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila central nervous system midline cells [13].
• Similar results were obtained when these responses were measured in strains where the larval photoreceptor neurons were ablated by mutations in the glass (gl) gene or by the targeted expression of the cell death gene head involution defective (hid) [14].
• Electron microscopy shows that autophagy is normally induced in fat body, midgut and salivary gland cells of homozygous mutant larvae, suggesting that Hid is not required for autophagy itself [15].

Associations of W with chemical compounds

• Nevertheless, interaction with Hid is not sufficient for Op-IAP to inhibit apoptosis induced by Hid overexpression or by treatment with actinomycin D, indicating that additional sequence elements are required for the anti-apoptotic function of Op-IAP [16].

Regulatory relationships of W

• The central cell death regulators Reaper and Hid induce apoptosis very rapidly by inhibiting DIAP1 function [17].
• A half reduction of the reaper, head involution defective and grim gene dose suppressed this DREF-induced notching wing phenotype [18].

Other interactions of W

• We found that mutations in peanut, which encodes a Drosophila homologue of ARTS, can dominantly suppress cell killing by Reaper, Hid and Grim, indicating that peanut acts downstream or in parallel to these [19].
• In Drosophila melanogaster, the induction of apoptosis requires three closely linked genes, reaper (rpr), head involution defective (hid), and grim [20].
• Here, we report the isolation of a mutant allele of the Drosophila effector caspase drICE as a strong suppressor of hid- (head involution defective-) induced apoptosis [21].
• Our data suggest that Wg signaling modulates Hid activity and that Hid regulates programmed cell death in a dose-sensitive fashion [22].
• From these regions and from additional candidate genes tested we identified four genes that suppress arm: dTCF, puckered, head involution defective (hid), and Dpresenilin [22].

References