Alternative titles; symbolsBCL2-INTERACTING PROTEINDP5HGNC Approved Gene Symbol: HRKCytogenetic location: 12q24.22 Genomic coordinates (GRCh38): 12:116,856,1...
Alternative titles; symbols
HGNC Approved Gene Symbol: HRK
Cytogenetic location: 12q24.22 Genomic coordinates (GRCh38): 12:116,856,143-116,881,440 (from NCBI)
Harakiri is a member of the BCL2 (151430) gene family, which encode apoptosis regulatory proteins. Some members of this family, including BCL2 and BCLXL (see 600039), function in repressing apoptosis, while others promote cell death (Inohara et al., 1997).
▼ Cloning and Expression
Using a yeast 2-hybrid screen with BCL2 as bait, Inohara et al. (1997) isolated HeLa cell cDNAs encoding a protein that they designated 'harakiri' (HRK). The predicted 91-amino acid protein lacked significant homology to other BCL2 family members except for an 8-amino acid region that was similar to the BCL2 homology domain-3 (BH3) motif of BIK (603392). Yeast 2-hybrid studies and coimmunoprecipitation studies with mammalian cell extracts indicated that HRK interacted with BCL2 and BCLXL, but not with the death-promoting BCL2-related proteins BAX (600040), BAK (600516), or BCLXS (see 600039). By immunofluorescence, the authors determined that HRK was localized to membranes of intracellular organelles in a pattern similar to that previously reported for BCL2 and BCLXL. Expression of HRK in mammalian cells induced rapid cell death, which was repressed by BCL2 and BCLXL. Inohara et al. (1997) found that deletion of the BH3 region abolished the ability of HRK to interact with BCL2 or BCLXL and eliminated or greatly reduced HRK killing activity. The authors suggested that HRK activates cell death at least in part by interacting with and inhibiting the protection afforded by BCL2 and BCLXL. Northern blot analysis revealed that the 0.7-kb HRK mRNA was expressed in all lymphoid tissues tested, with the strongest expression in bone marrow and spleen. The HRK transcript was also detected in pancreas.
▼ Animal Model
Kalinec et al. (2005) demonstrated that supplementation of pregnant guinea pigs with L-carnitine prevented neonatal mortality and gentamicin-induced sensorineural hearing loss (see 580000) in their offspring. Experiments with auditory cell lines showed that gentamicin-induced toxicity was mediated by activation of the MAPK (176948) signaling pathway through upregulation of Hrk. L-carnitine prevented gentamicin-induced upregulation of Hrk and apoptosis via JNK1 (MAPK8; 601158). Studies with small interfering RNA (siRNA) showed that Hrk upregulation was necessary for gentamicin-induced apoptosis.