CIAP1 (Homo sapiens)

Description [+]

Synonyms: CIAP1, BIRC2, CIAP1, HIAP-2, MIHB, RNF48
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: Baculoviral IAP repeat-containing protein 2 (Inhibitor of apoptosis protein 2)(HIAP-2)(C-IAP1)(TNFR2-TRAF-signaling complex protein 2)(IAP homolog B)(RING finger protein 48)
Family: BIR-containing protein : IAP
Process: apoptosis, immunity, necroptosis,
Pathways: TNF/NF-kappaB signaling,
Criteria: manually curated
Curator comment:
Mouse ortholog(s): cIAP1 Birc2
WIKI: CIAP1-H_sapiens

References [+]

The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
Eckelman BP, Salvesen GS
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not. J Biol Chem. 2006 Feb 10;281(6):3254-60. Epub 2005 Dec 8.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J
XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer. Cell. 2007 Nov 16;131(4):682-93.

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
Varfolomeev E,Blankenship JW,Wayson SM,Fedorova AV,Kayagaki N,Garg P,Zobel K,Dynek JN,Elliott LO,Wallweber HJ,Flygare JA,Fairbrother WJ,Deshayes K,Dixit VM,Vucic D
Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway. Cell. 2007 Nov 16;131(4):669-81.

An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer.
Zender L,Xue W,Zuber J,Semighini CP,Krasnitz A,Ma B,Zender P,Kubicka S,Luk JM,Schirmacher P,McCombie WR,Wigler M,Hicks J,Hannon GJ,Powers S,Lowe SW
Cancers are highly heterogeneous and contain many passenger and driver mutations. To functionally identify tumor suppressor genes relevant to human cancer, we compiled pools of short hairpin RNAs (shRNAs) targeting the mouse orthologs of genes recurrently deleted in a series of human hepatocellular carcinomas and tested their ability to promote tumorigenesis in a mosaic mouse model. In contrast to randomly selected shRNA pools, many deletion-specific pools accelerated hepatocarcinogenesis in mice. Through further analysis, we identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encodes a nuclear export protein whose substrate, EIF5A2, is amplified in human tumors, is required for proliferation of XPO4-deficient tumor cells, and promotes hepatocellular carcinoma in mice. Our results establish the feasibility of in vivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome. Cell. 2008 Nov 28;135(5):852-64. Epub 2008 Nov 13.

References from Mouse ortholog(s):

Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2.
Bertrand MJ, Doiron K, Labbe K, Korneluk RG, Barker PA, Saleh M
Cellular inhibitor of apoptosis proteins (cIAPs) block apoptosis, but their physiological functions are still under investigation. Here, we report that cIAP1 and cIAP2 are E3 ubiquitin ligases that are required for receptor-interacting protein 2 (RIP2) ubiquitination and for nucleotide-binding and oligomerization (NOD) signaling. Macrophages derived from Birc2(-/-) or Birc3(-/-) mice, or colonocytes depleted of cIAP1 or cIAP2 by RNAi, were defective in NOD signaling and displayed sharp attenuation of cytokine and chemokine production. This blunted response was observed in vivo when Birc2(-/-) and Birc3(-/-) mice were challenged with NOD agonists. Defects in NOD2 signaling are associated with Crohn's disease, and muramyl dipeptide (MDP) activation of NOD2 signaling protects mice from experimental colitis. Here, we show that administration of MDP protected wild-type but not Ripk2(-/-) or Birc3(-/-) mice from colitis, confirming the role of the cIAPs in NOD2 signaling in vivo. This discovery provides therapeutic opportunities in the treatment of NOD-dependent immunologic and inflammatory diseases. Immunity. 2009 Jun 19;30(6):789-801. Epub 2009 May 21.

The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV
The 75 kDa tumor necrosis factor receptor (TNFR2) transduces extracellular signals via receptor-associated cytoplasmic proteins. Two of these signal transducers, TRAF1 and TRAF2, were isolated and characterized previously. We report here the biochemical purification and subsequent molecular cloning of two novel TNFR2-associated proteins, designated c-IAP1 and c-IAP2, that are closely related mammalian members of the inhibitor of apoptosis protein (IAP) family originally identified in baculoviruses. The viral and cellular IAPs contain N-terminal baculovirus IAP repeat (BIR) motifs and a C-terminal RING finger. The c-IAPs do not directly contact TNFR2, but rather associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain. The recruitment of c-IAP1 or c-IAP2 to the TNFR2 signaling complex requires a TRAF2-TRAF1 heterocomplex. Cell. 1995 Dec 29;83(7):1243-52.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	BIR	49	114
PFAM A	BIR	187	251
PFAM A	BIR	272	337
PFAM A	CARD	458	542

Protein sequence [+]

Structure links:

Smartdomain prediction information: SM00238
Smartdomain prediction information: SM00114
Smartdomain prediction information: SM00184
Prosite motif and domain information: PS01282
Profile motif and domain profile information: PS50324
Profile motif and domain profile information: PS50209
Profile motif and domain profile information: PS50143
Profile motif and domain profile information: PS50089
Interpro domain information: Q13490
PFAM domain and domain family information: Q13490
Protein 3D structures from PDB: 1QBH 3D9T

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL006633-PA	orthology	Aedes
Q5MM83_AEDAE	orthology	Aedes
IAP4	orthology	Anopheles
IAP3	orthology	Anopheles
A_gambiae_AGAP007293-PA	orthology	Anopheles
BIR_CHICK	orthology	Chicken
BIR_CHICK	orthology	Chicken
BIRC2	orthology	Chimpanzee
BIRC2	orthology	Chimpanzee
C_intestinalis_ENSCINP00000000466	orthology	Ciona
NA	orthology	Ciona
C_intestinalis_ENSCINP00000000487	orthology	Ciona
C_intestinalis_ENSCINP00000000510	orthology	Ciona
C_intestinalis_ENSCINP00000002256	orthology	Ciona
C_intestinalis_ENSCINP00000002312	orthology	Ciona
C_intestinalis_ENSCINP00000005161	orthology	Ciona
C_intestinalis_ENSCINP00000009820	orthology	Ciona
C_intestinalis_ENSCINP00000010449	orthology	Ciona
C_intestinalis_ENSCINP00000011648	orthology	Ciona
C_intestinalis_ENSCINP00000020067	orthology	Ciona
NA	orthology	Ciona
C_intestinalis_ENSCINP00000021651	orthology	Ciona
C_intestinalis_ENSCINP00000000045	orthology	Ciona
IPI00824732.2	orthology	Cow
Q38JA8_CANFA	orthology	Dog
Q38JA8_CANFA	orthology	Dog
th	orthology	Fly
Iap2	orthology	Fly
Iap2	orthology	Fly
BIRC3	orthology	Fugu
BIRC3	orthology	Fugu
BIRC3	orthology	Gasterosteus
BIRC3	orthology	Gasterosteus
BIRC2	orthology	Gorilla
BIRC2	orthology	Gorilla
BIRC2	orthology	Horse
BIRC2	orthology	Horse
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
BIRC2	orthology	Macaca
BIRC2	orthology	Macaca
BIRC3	orthology	Medaka
M_domestica_ENSMODP00000000728	orthology	Monodelphis
XM_001362587.1	orthology	Monodelphis
M_domestica_ENSMODP00000000705	orthology	Monodelphis
M_domestica_ENSMODP00000000705	orthology	Monodelphis
cIAP1	orthology	Mouse
Birc2	orthology	Mouse
Q5R9T1_PONPY	orthology	Orangutan
Q5R9T1_PONPY	orthology	Orangutan
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000014265	orthology	Rabbit
Birc2	orthology	Rat
NP_068520.2	orthology	Rat
BIRC3	orthology	Tetraodon
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
birc3	orthology	Xenopus
birc3	orthology	Xenopus
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
T_guttata_ENSTGUP00000013125	orthology	Zebra finch
BIRC2	orthology	Zebra finch
birc2	orthology	Zebrafish
birc2	orthology	Zebrafish
BIRC7	paralogy	Chicken
IPI00603248.2	paralogy	Chicken
NP_989919.1	paralogy	Chicken
NP_989919.1	paralogy	Chicken
P_troglodytes_ENSPTRP00000048273	paralogy	Chimpanzee
XM_001156604.1	paralogy	Chimpanzee
BIRC3	paralogy	Chimpanzee
BIRC3	paralogy	Chimpanzee
BIRC8_PANTR	paralogy	Chimpanzee
XR_021305.1	paralogy	Chimpanzee
XR_021305.1	paralogy	Chimpanzee
XIAP	paralogy	Chimpanzee
XIAP	paralogy	Chimpanzee
IPI00689691.3	paralogy	Cow
IPI00689691.3	paralogy	Cow
NP_001030370.1	paralogy	Cow
NP_001030370.1	paralogy	Cow
Q8WMY4_BOVIN	paralogy	Cow
Q8WMY4_BOVIN	paralogy	Cow
BIRC7	paralogy	Dog
BIRC7	paralogy	Dog
BIRC3_CANFA	paralogy	Dog
BIRC3_CANFA	paralogy	Dog
Q38IV1_CANFA	paralogy	Dog
Q38IV1_CANFA	paralogy	Dog
BIRC8	paralogy	Fugu
XIAP	paralogy	Fugu
BIRC7	paralogy	Fugu
BIRC7	paralogy	Fugu
BIRC7	paralogy	Gasterosteus
BIRC7	paralogy	Gasterosteus
BIRC8	paralogy	Gasterosteus
XIAP	paralogy	Gasterosteus
BIRC3	paralogy	Gorilla
BIRC8	paralogy	Gorilla
BIRC7	paralogy	Gorilla
BIRC7	paralogy	Gorilla
XIAP	paralogy	Gorilla
XIAP	paralogy	Gorilla
E_caballus_ENSECAP00000002314	paralogy	Horse
XP_001504091.2	paralogy	Horse
BIRC3	paralogy	Horse
BIRC3	paralogy	Horse
BIRC8	paralogy	Horse
XIAP	paralogy	Horse
BIRC7	paralogy	Horse
BIRC7	paralogy	Horse
BIRC1	paralogy	Human
NAIP	paralogy	Human
BIRC7	paralogy	Human
BIRC7	paralogy	Human
BIRC8	paralogy	Human
BIRC8	paralogy	Human
XIAP	paralogy	Human
XIAP	paralogy	Human
BIRC3	paralogy	Human
BIRC3	paralogy	Human
BIRC7	paralogy	Lyzard
BIRC7	paralogy	Lyzard
A_carolinensis_ENSACAP00000009897	paralogy	Lyzard
A_carolinensis_ENSACAP00000009897	paralogy	Lyzard
A_carolinensis_ENSACAP00000011315	paralogy	Lyzard
A_carolinensis_ENSACAP00000011315	paralogy	Lyzard
BIRC3	paralogy	Macaca
BIRC3	paralogy	Macaca
BIRC7	paralogy	Macaca
BIRC7	paralogy	Macaca
BIRC8	paralogy	Medaka
XIAP	paralogy	Medaka
BIRC7	paralogy	Medaka
BIRC7	paralogy	Medaka
M_domestica_ENSMODP00000018715	paralogy	Monodelphis
XM_001364568.1	paralogy	Monodelphis
BIRC7	paralogy	Monodelphis
BIRC7	paralogy	Monodelphis
cIAP2	paralogy	Mouse
Birc3	paralogy	Mouse
Naip1	paralogy	Mouse
Naip4	paralogy	Mouse
Naip5	paralogy	Mouse
Naip5	paralogy	Mouse
Birc7	paralogy	Mouse
Birc7	paralogy	Mouse
Xiap	paralogy	Mouse
Xiap	paralogy	Mouse
Birc1-rs1	paralogy	Mouse
Naip6	paralogy	Mouse
Naip2	paralogy	Mouse
Naip2	paralogy	Mouse
BIRC3	paralogy	Orangutan
BIRC3	paralogy	Orangutan
BIRC7	paralogy	Orangutan
BIRC7	paralogy	Orangutan
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
XIAP	paralogy	Orangutan
XIAP	paralogy	Orangutan
O_anatinus_ENSOANP00000006435	paralogy	Ornithorhynchus
O_anatinus_ENSOANP00000006435	paralogy	Ornithorhynchus
BIRC7	paralogy	Rabbit
O_cuniculus_ENSOCUP00000008505	paralogy	Rabbit
XIAP	paralogy	Rabbit
BIRC3	paralogy	Rabbit
BIRC3	paralogy	Rabbit
Birc3	paralogy	Rat
NP_076477.2	paralogy	Rat
Birc4	paralogy	Rat
XIAP_RAT	paralogy	Rat
RGD1559914_predicted	paralogy	Rat
Q8R4U8_RAT	paralogy	Rat
BIRC7	paralogy	Tetraodon
BIRC7	paralogy	Tetraodon
BIRC8	paralogy	Tetraodon
XIAP	paralogy	Tetraodon
K11D12.9	paralogy	Worm
X_tropicalis_ENSXETP00000034890	paralogy	Xenopus
birc4	paralogy	Xenopus
birc4	paralogy	Xenopus
X_tropicalis_ENSXETP00000057704	paralogy	Xenopus
X_tropicalis_ENSXETP00000016312	paralogy	Xenopus
X_tropicalis_ENSXETP00000016315	paralogy	Xenopus
BIRC7	paralogy	Xenopus
BIRC7	paralogy	Xenopus
T_guttata_ENSTGUP00000003825	paralogy	Zebra finch
XIAP	paralogy	Zebra finch
BIRC7	paralogy	Zebra finch
BIRC7	paralogy	Zebra finch
birc4	paralogy	Zebrafish
xiap	paralogy	Zebrafish
BIRC7	paralogy	Zebrafish
zgc:165605	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0001666	response to hypoxia	biological_proccess	IEA
GO:0001890	placenta development	biological_proccess	IEA
GO:0007166	cell surface receptor linked signal transduction	biological_proccess	TAS
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB cascade	biological_proccess	IEP
GO:0042981	regulation of apoptosis	biological_proccess	IEA
GO:0014070	response to organic cyclic substance	biological_proccess	IEA
GO:0051591	response to cAMP	biological_proccess	IEA
GO:0010243	response to organic nitrogen	biological_proccess	IEA
GO:0051291	protein heterooligomerization	biological_proccess	IEA
GO:0045471	response to ethanol	biological_proccess	IEA
GO:0005515	protein binding	mollecular_function	IPI
GO:0046872	metal ion binding	mollecular_function	IEA
GO:0008270	zinc ion binding	mollecular_function	IEA
GO:0005515	protein binding	mollecular_function	IEA
GO:0005829	cytosol	cell_component	EXP
GO:0005737	cytoplasm	cell_component	IEA
GO:0005622	intracellular	cell_component	IEA
GO:0005634	nucleus	cell_component	IEA
GO:0043234	protein complex	cell_component	IEA
GO:0045121	membrane raft	cell_component	IEA
GO:0001741	XY body	cell_component	IEA

Check GO Evidence Codes here

KEGG Pathways [+]

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :590
Gene related info from GeneCards [?] : cIAP1
Ensembl genome browser [?] : ENSG00000110330
Expression info from Arrayexpress [?] : ENSG00000110330
Protein expression from Protein Atlas: [?] ENSG00000110330
Community gene edition from Wikigenes: [?] 329

Protein related links:

Uniprot protein info: Q13490
PIR protein info: Q13490
Protein interactions from IntAct: Q13490

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

OMIM gene information: 601712
OMIM disease information:

Other links

entrezgene: 329
refseq_dna: NM_001166
refseq_peptide: NP_001157

Click on [?] for more information.