Disease relevance of th

• 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 [1].
• The Drosophila inhibitor of apoptosis (IAP) DIAP2 is dispensable for cell survival, required for the innate immune response to gram-negative bacterial infection, and can be negatively regulated by the reaper/hid/grim family of IAP-binding apoptosis inducers [2].
• Here, we generated synthetic Smac peptide which possesses an IAP-binding domain and Drosophila antennapaedia penetration sequence, and examined whether it enhances the effect of the chemotherapeutic agent etoposide in the human glioblastoma cell line [3].

High impact information on th

• Drosophila IAP1 (DIAP1) is an endogenous caspase inhibitor that is crucial for regulating cell death during development [4].
• We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation [4].
• Yorkie is known to activate Cyclin E (CycE) and the apoptosis inhibitor DIAP1 [5].
• However, DmIKK epsilon-mediated degradation of DIAP1 does not regulate apoptosis as might be predicted but instead regulates actin dynamics, cell morphology, and the differentiation of sensory organ precursor cells [6].
• Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1 [7].

Biological context of th

• In addition, that analysis of loss-of-function mutations demonstrates that th is necessary to block apoptosis very early in embryonic development [8].
• The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID [9].
• These observations define two mechanisms through which DIAP1 ubiquitination controls cell death: first, increased ubiquitination promotes degradation directly; second, a decrease in global protein synthesis results in a differential loss of short-lived proteins such as DIAP1 [10].
• Here, using RNA interference, we showed that down-regulation of DIAP1 is sufficient to induce cell death in Drosophila S2 cells [11].
• Drosophila IAP1 (DIAP1) inhibits cell death to facilitate normal embryonic development [11].

Anatomical context of th

• In cultured cells, Morgue induced apoptosis that was suppressed by DIAP1 [12].
• The anti-apoptotic activities of two baculovirus IAPs, OpIAP and CpIAP, were directly compared with that of two Drosophila IAPs, DIAP1 and DIAP2, in the same insect cell line, SF-21 cells [13].

Associations of th with chemical compounds

• A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila [14].
• Like OpIAP and CpIAP, DIAP1 inhibited actinomycin D-induced apoptosis and apoptosis induced by Doom [13].
• Moreover, a decrease in VG or addition of aminopterin, a specific DHFR inhibitor, shift the dorso-ventral boundary cells of the disc to a cell death sensitive state that is correlated with reaper induction and DIAP1 downregulation [15].
• 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 [16].
• Recent reports have demonstrated that shortly after the initiation of apoptosis in S2 cells, DIAP1 is cleaved following aspartate residue Asp-20 by the effector caspase DrICE [16].

Physical interactions of th

• Mature Jafrac2 interacts genetically and biochemically with DIAP1 and promotes cell death in tissue culture cells and the Drosophila developing eye [17].
• UBCD1 and Rpr specifically bind to DIAP1 and stimulate DIAP1 auto-ubiquitination in vitro [18].
• This recognition is essential for DIAP1 binding to Dronc, and for targeting Dronc for ubiquitination [19].
• Instead, a second IAP-binding domain, distinct from the R3, was identified at the C terminus of Reaper that bound to DIAP1 but failed to trigger apoptosis [20].

Enzymatic interactions of th

• We found that DIAP1 is cleaved by a caspase early after the initiation of apoptosis [21].

Regulatory relationships of th

• Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms [10].
• Silencing of diap1 or treatment with UV light induced DRONC processing, which occurred in two steps [22].
• Here, we present an analysis of loss-of-function and gain-of-function alleles of th, which indicates that additional domains of TH/DIAP1 are necessary for its ability to inhibit death induced by RPR, GRIM, and HID [8].
• Because loss of DIAP1 is sufficient to promote caspase activation, these mechanisms should promote apoptosis [10].
• We conclude that D-IAP1 is capable of inhibiting the activation of drICE as well as inhibiting apoptosis induced by the active form of drICE [23].

Other interactions of th

• Observations with Grim suggest that one mechanism by which these proteins produce a relative decrease in DIAP1 levels is to promote a general suppression of protein translation [10].
• Co-silencing of dronc or dark largely suppressed this apoptosis, indicating that DIAP1 is normally required to inhibit an activity dependent on these proteins [22].
• Our data suggest that DIAP1 instability, mediated through caspase activity and subsequent exposure of the N-end rule pathway, is essential for suppression of apoptosis [24].
• It has been proposed that RPR, GRIM, and HID induce apoptosis by binding and inactivating TH/DIAP1 [8].
• RNA interference studies in Drosophila embryos also demonstrated that the action of Dark is epistatic to that of DIAP1 in this cell death pathway [11].

Analytical, diagnostic and therapeutic context of th

• Dissection of DIAP1 functional domains via a mutant replacement strategy [21].
• Whereas Sav and Hpo normally restrict cellular quantities of the Drosophila inhibitor of apoptosis protein DIAP1, overexpression of Hpo destabilizes DIAP1 in cell culture [25].

References