Apoptosis Database

Description [+]

Synonyms: HRK, DP5
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: Activator of apoptosis harakiri (Neuronal death protein DP5)(BH3-interacting domain-containing protein 3) [Source:UniProtKB/Swiss-Prot;Acc:O00198]
Family: Bcl-2 family : BH3-only
Process: apoptosis,
Pathways: intrinsic pathway,
Criteria: manually curated
Curator comment:
Mouse ortholog(s): DP5
WIKI: HRK-H_sapiens

References [+]

harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L).
Inohara N, Ding L, Chen S, Nunez G
Programmed cell death is essential in organ development and tissue homeostasis and its deregulation is associated with the development of several diseases in mice and humans. The precise mechanisms that control cell death have not been elucidated fully, but it is well established that this form of cellular demise is regulated by a genetic program which is activated in the dying cell. Here we report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis. The product of harakiri, Hrk, physically interacts with the death-repressor proteins Bcl-2 and Bcl-X(L), but not with death-promoting homologs, Bax or Bak. Hrk lacks conserved BH1 and BH2 regions and significant homology to Bcl-2 family members or any other protein, except for a stretch of eight amino acids that exhibits high homology with BH3 regions. Expression of Hrk induces cell death which is inhibited by Bcl-2 and Bcl-X(L). Deletion of 16 amino acids including the conserved BH3 region abolished the ability of Hrk to interact with Bcl-2 and Bcl-X(L) in mammalian cells. Moreover, the killing activity of this mutant form of Hrk (Hrk deltaBH3) was eliminated or dramatically reduced, suggesting that Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by Bcl-2 and Bcl-X(L). Because Hrk lacks conserved BH1 and BH2 domains that define Bcl-2 family members, we propose that Hrk and Bik/Nbk, another BH3-containing protein that activates apoptosis, represent a novel class of proteins that regulate apoptosis by interacting selectively with survival-promoting Bcl-2 and Bcl-X(L). EMBO J. 1997 Apr 1;16(7):1686-94.

Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death.
Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M
To study the molecular mechanisms underlying neuronal programmed cell death (PCD), we performed differential display screening for genes, the expression of which was induced during PCD in the sympathetic neuron culture model deprived of NGF. We cloned a gene encoding a novel polypeptide (DP5) which consisted of 92 amino acids. DP5 polypeptide had no homology with any other known protein and contained no motif that would indicate its putative biochemical functions. DP5 mRNA levels peaked at 15 h after nerve growth factor withdrawal, concurrent with the time at which neurons were committed to die. The induction of DP5 gene expression was blocked when cell death was rescued by treatment with cycloheximide, KCl, or the cyclic AMP analogue CPTcAMP. Overexpression of the full-length DP5 in cultured sympathetic neurons was in itself sufficient to induce apoptosis. These results suggest that DP5 plays a role in programmed neuronal death. J Biol Chem. 1997 Jul 25;272(30):18842-8.

References from Mouse ortholog(s):

Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis.
Coultas L, Terzano S, Thomas T, Voss A, Reid K, Stanley EG, Scott CL, Bouillet P, Bartlett P, Ham J, Adams JM, Strasser A
The pro-apoptotic BH3-only members of the Bcl2 family, crucial initiators of cell death, are activated by a diverse array of developmental cues or experimentally applied stress stimuli. We have investigated, through gene targeting in mice, the biological roles for the BH3-only family member HRK (also known as DP5) in apoptosis regulation. Hrk gene expression was found to be restricted to cells and tissues of the central and peripheral nervous systems. Sensory neurons from mice lacking Hrk were less sensitive to apoptosis induced by nerve growth factor (NGF) withdrawal, consistent with the induction of Hrk following NGF deprivation. By contrast, cerebellar granule neurons that upregulate Hrk upon transfer to low-K+ medium underwent apoptosis normally under these conditions in the absence of Hrk. Furthermore, loss of Hrk was not sufficient to rescue the neuronal degeneration in lurcher mutant mice. Despite previous reports, no evidence was found for Hrk expression or induction in growth-factor-dependent haematopoietic cell lines following withdrawal of their requisite cytokine, and haematopoietic progenitors lacking HRK died normally in response to cytokine deprivation. These results demonstrate that HRK contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal populations but is dispensable for apoptosis of haematopoietic cells. J Cell Sci. 2007 Jun 15;120(Pt 12):2044-52. Epub 2007 May 29.

harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L).
Inohara N, Ding L, Chen S, Nunez G
Programmed cell death is essential in organ development and tissue homeostasis and its deregulation is associated with the development of several diseases in mice and humans. The precise mechanisms that control cell death have not been elucidated fully, but it is well established that this form of cellular demise is regulated by a genetic program which is activated in the dying cell. Here we report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis. The product of harakiri, Hrk, physically interacts with the death-repressor proteins Bcl-2 and Bcl-X(L), but not with death-promoting homologs, Bax or Bak. Hrk lacks conserved BH1 and BH2 regions and significant homology to Bcl-2 family members or any other protein, except for a stretch of eight amino acids that exhibits high homology with BH3 regions. Expression of Hrk induces cell death which is inhibited by Bcl-2 and Bcl-X(L). Deletion of 16 amino acids including the conserved BH3 region abolished the ability of Hrk to interact with Bcl-2 and Bcl-X(L) in mammalian cells. Moreover, the killing activity of this mutant form of Hrk (Hrk deltaBH3) was eliminated or dramatically reduced, suggesting that Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by Bcl-2 and Bcl-X(L). Because Hrk lacks conserved BH1 and BH2 domains that define Bcl-2 family members, we propose that Hrk and Bik/Nbk, another BH3-containing protein that activates apoptosis, represent a novel class of proteins that regulate apoptosis by interacting selectively with survival-promoting Bcl-2 and Bcl-X(L). EMBO J. 1997 Apr 1;16(7):1686-94.

Structure & Sequence [+]

Evolution [+]

Name	Relationship	Species
HRK	orthology	Chimpanzee
HRK	orthology	Dog
HRK	orthology	Monodelphis
DP5	orthology	Mouse
HRK	orthology	Orangutan
HRK	orthology	Rabbit
Bid3	orthology	Rat

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0042981	regulation of apoptosis	biological_proccess	IEA
GO:0006917	induction of apoptosis	biological_proccess	TAS
GO:0008634	negative regulation of survival gene product expression	biological_proccess	TAS
GO:0043525	positive regulation of neuron apoptosis	biological_proccess	IEA
GO:0051365	cellular response to potassium ion starvation	biological_proccess	IEA
GO:0005515	protein binding	mollecular_function	IPI
GO:0005515	protein binding	mollecular_function	IEA

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :5185
Gene related info from GeneCards [?] : HRK
Ensembl genome browser [?] : ENSG00000135116
Expression info from Arrayexpress [?] : ENSG00000135116
Protein expression from Protein Atlas: [?] ENSG00000135116
Community gene edition from Wikigenes: [?] 8739

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 603447
OMIM disease information:

Other links

entrezgene: 8739
refseq_dna: NM_003806
refseq_peptide: NP_003797

Click on [?] for more information.

HRK (Homo sapiens)