Disease relevance of HRK

• Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer [1].
• Aberrant methylation of HRK was also frequently detected in primary colorectal cancers that showed methylation of multiple genes, including p16INK4A and hMLH1, and was associated with wild-type p53 [1].
• Our aim is to verify the alterations in the HRK gene in primary central nervous system lymphomas (PCNSLs) [2].
• Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas [3].
• Confocal laser microscopy demonstrated that Hrk expression coincided with immunoreactivities against HIV-1 and Cryptococcus neoformans [4].

High impact information on HRK

• Here we report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis [5].
• The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neuronal apoptosis following exposure to amyloid beta protein [6].
• DP5, which contains a BH3 domain, was cloned as a neuronal apoptosis-inducing gene [6].
• Induction of DP5 gene expression was blocked by nifedipine, an inhibitor of L-type voltage-dependent calcium channels, and dantrolene, an inhibitor of calcium release from the endoplasmic reticulum [6].
• HRK expression was restored by treatment with a methyltransferase inhibitor, 5-aza-deoxycytidine, and enhanced further by addition of histone deacetylase inhibitor trichostatin A or depsipeptide [1].

Chemical compound and disease context of HRK

• EXPERIMENTAL DESIGN: Methylation of HRK was evaluated by bisulfite-PCR and bisulfite sequencing in a group of colorectal and gastric cancer cell lines and primary cancers [1].
• Upregulation of the pro-apoptotic BH3-only peptide harakiri in spinal neurons of amyotrophic lateral sclerosis patients [7].
• When a promoter containing these elements is used to control the expression of the pro-apoptotic gene harakiri, the induction of cell death can be activated by estrogens and hypoxia, and inhibited by antiestrogens such as tamoxifen [8].

Biological context of HRK

• We found the proapoptotic gene HRK to be a target for hypermethylation in human cancers and examined the role of such methylation in silencing the gene's expression [1].
• Such restoration of HRK expression was well correlated with induction of apoptosis and enhancement of Adriamycin-induced apoptosis [1].
• RESULTS: The region around the HRK transcription start site was methylated in 36% of colorectal and 32% of gastric cancer cell lines and was closely associated with loss of expression in those cell types [1].
• To detect and identify the genetic alterations and methylation status of the HRK gene in human glioblastomas, we analyzed a cohort of astrocytic tumors for hypermethylation, loss of heterozygosity on 12q13.1, and gene expression [3].
• Our findings suggest that HRK is inactivated mainly by aberrant DNA methylation in astrocytic tumors and that reduced HRK expression contributes to the loss of apoptotic control in high-grade tumors [3].

Anatomical context of HRK

• Expression of apoptosis-related genes during human preimplantation embryo development: potential roles for the Harakiri gene product and Caspase-3 in blastomere fragmentation [9].
• Two T cell clones established from two other unrelated donors were specific for p193-204 in the context of DRB1*1401 and for p153-165 in the context of DP5, respectively [10].
• Immunoreactivity against Hrk was positive in perivascular macrophages infiltrated into some restricted lesions [4].
• The DT6/pDNAcomplex with smaller size mediated higher transgene expression in COS-7 cells than those prepared with DP5 or DI5 [11].

Associations of HRK with chemical compounds

• Hrk/DP5 is one of the mammalian BH3-only proteins implicated in a variety of physiological and pathological apoptosis, yet the molecular mechanism involved in Hrk-mediated apoptosis remains poorly understood [12].
• The results of substrate specificity and susceptibility to various protease inhibitors of DP5 and DF5 strongly suggested that they belonged to the chymotrypsin-like serine protease family [13].
• The enzymatically generated water-soluble dextrins (maltose and DP3, DP4, DP5, and DP6 dextrins) are the most effective in preserving crumb softness during bread storage [14].
• The LpFT2 recombinant protein expressed in yeast showed invertase and fructan exohydrolase-like activities with complete breakdown of sucrose, 1-kestose (DP3), 1,1-kestotetraose (DP4) and 1,1,1-kestopentaose (DP5) into glucose and fructose [15].

Regulatory relationships of HRK

• CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri [16].

Other interactions of HRK

• In PgR+ cell lines and in concordance with the protective effect, the pro-apoptotic HRK and BAK1 mRNAs were up-regulated after apoptosis induction, while they were no more induced in condition of protection against apoptosis after MPA treatment [17].

Analytical, diagnostic and therapeutic context of HRK

• DP5 mRNA was induced 6 h after treatment with A beta in cultured rat cortical neurons [6].
• Expression of Hrk mRNA was demonstrated in these cells by in situ hybridization, which indicated that Hrk is not phagocytosed material [4].
• Bcl-2, bcl-XL, bax, and DP5 mRNA expression were analyzed by RT-PCR [18].

References