TH (Drosophila melanogaster)
Description [+]
- Synonyms: TH, IAP1,INHIBITOR OF APOPTOSIS 1, THREAD
- Species: Metazoa;Bilateria;Ecdysozoa;Arthropoda;Hexapoda; Drosophila melanogaster
- Short gene description: NA
- Family: BIR-containing protein : IAP
- Process: apoptosis,
- Pathways:
- Criteria: manually curated
- Curator comment:
- Human ortholog(s): BIRC7 cIAP1 BIRC2 BIRC8 XIAP BIRC3
- WIKI: TH-D_melanogaster
References [+]
- Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death.
- Hay BA, Wassarman DA, Rubin GM
- Apoptotic cell death is a mechanism by which organisms eliminate superfluous or harmful cells. Expression of the cell death regulatory protein REAPER (RPR) in the developing Drosophila eye results in a small eye owing to excess cell death. We show that mutations in thread (th) are dominant enhancers of RPR-induced cell death and that th encodes a protein homologous to baculovirus inhibitors of apoptosis (IAPs), which we call Drosophila IAP1 (DIAP1). Overexpression of DIAP1 or a related protein, DIAP2, in the eye suppresses normally occurring cell death as well as death due to overexpression of rpr or head involution defective. IAP death-preventing activity localizes to the N-terminal baculovirus IAP repeats, a motif found in both viral and cellular proteins associated with death prevention. Cell. 1995 Dec 29;83(7):1253-62.
- References from Human ortholog(s):
- 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.
- X-linked IAP is a direct inhibitor of cell-death proteases.
- Deveraux QL, Takahashi R, Salvesen GS, Reed JC
- The inhibitor-of-apoptosis (IAP) family of genes has an evolutionarily conserved role in regulating programmed cell death in animals ranging from insects to humans. Ectopic expression of human IAP proteins can suppress cell death induced by a variety of stimuli, but the mechanism of this inhibition was previously unknown. Here we show that human X-chromosome-linked IAP directly inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. As the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis, our findings suggest how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors. Nature. 1997 Jul 17;388(6639):300-4.
- 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.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
| Source | Domain Name | Start | End |
|---|---|---|---|
| PFAM A | BIR | 47 | 111 |
| PFAM A | BIR | 229 | 294 |
Protein sequence [+]
th | Drosophila melanogaster | 7227 | length:438
MASVVADLPSYGPIAFDQVDNNTNATQLFKNNINKTRMNDLNREETRLKTFTDWPLDWLD
KRQLAQTGMYFTHAGDKVKCFFCGVEIGCWEQEDQPVPEHQRWSPNCPLLRRRTTNNVPI
NAEALDRILPPISYDICGANDSTLEMREHAYAEGVIPMSQLIQSIGMNAVNAAGSVTGTA
APQPRVTVATHASTATQATGDVQPETCRPSAASGNYFPQYPEYAIETARLRTFEAWPRNL
KQKPHQLAEAGFFYTGVGDRVRCFSCGGGLMDWNDNDEPWEQHALWLSQCRFVKLMKGQL
YIDTVAAKPVLAEEKEESSSIGGVAVASTQASEEEQQTSLSSEEAVSGDVAPSVAPTAAT
RIFNKIVEATAVATPSTNSSGSTSIPEEKLCKICYGAEYNTAFLPCGHVVACAKCASSVT
KCPLCRKPFTDVMRVYFS
KRQLAQTGMYFTHAGDKVKCFFCGVEIGCWEQEDQPVPEHQRWSPNCPLLRRRTTNNVPI
NAEALDRILPPISYDICGANDSTLEMREHAYAEGVIPMSQLIQSIGMNAVNAAGSVTGTA
APQPRVTVATHASTATQATGDVQPETCRPSAASGNYFPQYPEYAIETARLRTFEAWPRNL
KQKPHQLAEAGFFYTGVGDRVRCFSCGGGLMDWNDNDEPWEQHALWLSQCRFVKLMKGQL
YIDTVAAKPVLAEEKEESSSIGGVAVASTQASEEEQQTSLSSEEAVSGDVAPSVAPTAAT
RIFNKIVEATAVATPSTNSSGSTSIPEEKLCKICYGAEYNTAFLPCGHVVACAKCASSVT
KCPLCRKPFTDVMRVYFS
Structure links:
Evolution [+]
View protein alignment and tree with Jalview:
Explore tree at phylomeDB: Click here.
Homologs list [+]
| Name | Relationship | Species |
|---|---|---|
| Q5MM83_AEDAE | orthology | Aedes |
| IAP1 | orthology | Anopheles |
| BIRC7 | orthology | Chicken |
| IPI00603248.2 | orthology | Chicken |
| BIR_CHICK | orthology | Chicken |
| BIR_CHICK | orthology | Chicken |
| NP_989919.1 | orthology | Chicken |
| NP_989919.1 | orthology | Chicken |
| BIRC3 | orthology | Chimpanzee |
| BIRC3 | orthology | Chimpanzee |
| BIRC2 | orthology | Chimpanzee |
| BIRC2 | orthology | Chimpanzee |
| BIRC8_PANTR | orthology | Chimpanzee |
| XR_021305.1 | orthology | Chimpanzee |
| XR_021305.1 | orthology | Chimpanzee |
| XIAP | orthology | Chimpanzee |
| XIAP | orthology | Chimpanzee |
| C_intestinalis_ENSCINP00000000045 | orthology | Ciona |
| C_intestinalis_ENSCINP00000000047 | orthology | Ciona |
| 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 |
| NP_001030370.1 | orthology | Cow |
| NP_001030370.1 | orthology | Cow |
| Q8WMY4_BOVIN | orthology | Cow |
| Q8WMY4_BOVIN | orthology | Cow |
| BIRC7 | orthology | Dog |
| BIRC7 | orthology | Dog |
| Q38JA8_CANFA | orthology | Dog |
| Q38JA8_CANFA | orthology | Dog |
| BIRC3_CANFA | orthology | Dog |
| BIRC3_CANFA | orthology | Dog |
| Q38IV1_CANFA | orthology | Dog |
| Q38IV1_CANFA | orthology | Dog |
| BIRC8 | orthology | Fugu |
| XIAP | orthology | Fugu |
| BIRC7 | orthology | Fugu |
| BIRC7 | orthology | Fugu |
| BIRC3 | orthology | Fugu |
| BIRC3 | orthology | Fugu |
| BIRC7 | orthology | Gasterosteus |
| BIRC7 | orthology | Gasterosteus |
| BIRC8 | orthology | Gasterosteus |
| XIAP | orthology | Gasterosteus |
| BIRC3 | orthology | Gasterosteus |
| BIRC3 | orthology | Gasterosteus |
| BIRC3 | orthology | Gorilla |
| BIRC8 | orthology | Gorilla |
| BIRC2 | orthology | Gorilla |
| BIRC2 | orthology | Gorilla |
| BIRC7 | orthology | Gorilla |
| BIRC7 | orthology | Gorilla |
| XIAP | orthology | Gorilla |
| XIAP | orthology | Gorilla |
| BIRC2 | orthology | Horse |
| BIRC3 | orthology | Horse |
| BIRC3 | orthology | Horse |
| BIRC8 | orthology | Horse |
| XIAP | orthology | Horse |
| BIRC7 | orthology | Horse |
| BIRC7 | orthology | Horse |
| BIRC2 | orthology | Horse |
| BIRC7 | orthology | Human |
| BIRC7 | orthology | Human |
| cIAP1 | orthology | Human |
| BIRC2 | orthology | Human |
| BIRC8 | orthology | Human |
| BIRC8 | orthology | Human |
| XIAP | orthology | Human |
| XIAP | orthology | Human |
| BIRC3 | orthology | Human |
| BIRC3 | orthology | Human |
| BIRC7 | orthology | Lyzard |
| BIRC7 | orthology | Lyzard |
| A_carolinensis_ENSACAP00000011315 | orthology | Lyzard |
| A_carolinensis_ENSACAP00000011315 | orthology | Lyzard |
| A_carolinensis_ENSACAP00000012475 | orthology | Lyzard |
| A_carolinensis_ENSACAP00000012475 | orthology | Lyzard |
| BIRC3 | orthology | Macaca |
| BIRC3 | orthology | Macaca |
| BIRC2 | orthology | Macaca |
| BIRC2 | orthology | Macaca |
| BIRC7 | orthology | Macaca |
| BIRC7 | orthology | Macaca |
| BIRC3 | orthology | Medaka |
| BIRC8 | orthology | Medaka |
| XIAP | orthology | Medaka |
| BIRC7 | orthology | Medaka |
| BIRC7 | orthology | Medaka |
| M_domestica_ENSMODP00000000705 | orthology | Monodelphis |
| M_domestica_ENSMODP00000000705 | orthology | Monodelphis |
| M_domestica_ENSMODP00000000728 | orthology | Monodelphis |
| XM_001362587.1 | orthology | Monodelphis |
| M_domestica_ENSMODP00000018715 | orthology | Monodelphis |
| XM_001364568.1 | orthology | Monodelphis |
| BIRC7 | orthology | Monodelphis |
| BIRC7 | orthology | Monodelphis |
| Birc2 | orthology | Mouse |
| Birc7 | orthology | Mouse |
| Birc7 | orthology | Mouse |
| Xiap | orthology | Mouse |
| Xiap | orthology | Mouse |
| cIAP2 | orthology | Mouse |
| Birc3 | orthology | Mouse |
| cIAP1 | orthology | Mouse |
| XIAP | orthology | Orangutan |
| XIAP | orthology | Orangutan |
| BIRC3 | orthology | Orangutan |
| BIRC3 | orthology | Orangutan |
| Q5R9T1_PONPY | orthology | Orangutan |
| Q5R9T1_PONPY | orthology | Orangutan |
| BIRC7 | orthology | Orangutan |
| BIRC7 | orthology | Orangutan |
| O_anatinus_ENSOANP00000006435 | orthology | Ornithorhynchus |
| O_anatinus_ENSOANP00000006435 | orthology | Ornithorhynchus |
| O_anatinus_ENSOANP00000016616 | orthology | Ornithorhynchus |
| O_anatinus_ENSOANP00000016616 | orthology | Ornithorhynchus |
| BIRC7 | orthology | Rabbit |
| O_cuniculus_ENSOCUP00000008505 | orthology | Rabbit |
| XIAP | orthology | Rabbit |
| BIRC3 | orthology | Rabbit |
| BIRC3 | orthology | Rabbit |
| O_cuniculus_ENSOCUP00000011948 | orthology | Rabbit |
| O_cuniculus_ENSOCUP00000011948 | orthology | Rabbit |
| O_cuniculus_ENSOCUP00000014265 | orthology | Rabbit |
| Birc3 | orthology | Rat |
| NP_076477.2 | orthology | Rat |
| Birc4 | orthology | Rat |
| XIAP_RAT | orthology | Rat |
| Birc2 | orthology | Rat |
| NP_068520.2 | orthology | Rat |
| BIRC3 | orthology | Tetraodon |
| BIRC8 | orthology | Tetraodon |
| XIAP | orthology | Tetraodon |
| BIRC7 | orthology | Tetraodon |
| BIRC7 | orthology | Tetraodon |
| BIRC7 | orthology | Xenopus |
| BIRC7 | orthology | Xenopus |
| X_tropicalis_ENSXETP00000030727 | orthology | Xenopus |
| X_tropicalis_ENSXETP00000030727 | orthology | Xenopus |
| birc4 | orthology | Xenopus |
| birc4 | orthology | Xenopus |
| birc3 | orthology | Xenopus |
| birc3 | orthology | Xenopus |
| T_guttata_ENSTGUP00000003825 | orthology | Zebra finch |
| XIAP | orthology | Zebra finch |
| BIRC7 | orthology | Zebra finch |
| BIRC7 | orthology | Zebra finch |
| T_guttata_ENSTGUP00000013125 | orthology | Zebra finch |
| BIRC2 | orthology | Zebra finch |
| birc4 | orthology | Zebrafish |
| xiap | orthology | Zebrafish |
| birc2 | orthology | Zebrafish |
| birc2 | orthology | Zebrafish |
| BIRC7 | orthology | Zebrafish |
| zgc:165605 | orthology | Zebrafish |
| A_aegypti_AAEL001765-PA | paralogy | Aedes |
| A_aegypti_AAEL006633-PA | paralogy | Aedes |
| IAP4 | paralogy | Anopheles |
| IAP3 | paralogy | Anopheles |
| A_gambiae_AGAP007293-PA | paralogy | Anopheles |
| IAP2 | paralogy | Anopheles |
| IAP4 | paralogy | Anopheles |
| MIB1 | paralogy | Chicken |
| P_troglodytes_ENSPTRP00000048273 | paralogy | Chimpanzee |
| XM_001156604.1 | paralogy | Chimpanzee |
| IPI00689691.3 | paralogy | Cow |
| IPI00689691.3 | paralogy | Cow |
| IPI00695641.3 | paralogy | Cow |
| Iap2 | paralogy | Fly |
| Iap2 | paralogy | Fly |
| E_caballus_ENSECAP00000002314 | paralogy | Horse |
| XP_001504091.2 | paralogy | Horse |
| BIRC1 | paralogy | Human |
| NAIP | paralogy | Human |
| A_carolinensis_ENSACAP00000009897 | paralogy | Lyzard |
| A_carolinensis_ENSACAP00000009897 | paralogy | Lyzard |
| MIB1 | paralogy | Monodelphis |
| Birc1-rs1 | paralogy | Mouse |
| Naip6 | paralogy | Mouse |
| Naip2 | paralogy | Mouse |
| Naip2 | paralogy | Mouse |
| Naip1 | paralogy | Mouse |
| Naip4 | paralogy | Mouse |
| Naip5 | paralogy | Mouse |
| Naip5 | paralogy | Mouse |
| P_pygmaeus_ENSPPYP00000017359 | paralogy | Orangutan |
| P_pygmaeus_ENSPPYP00000017359 | paralogy | Orangutan |
| RGD1559914_predicted | paralogy | Rat |
| Q8R4U8_RAT | paralogy | Rat |
| X_tropicalis_ENSXETP00000016312 | paralogy | Xenopus |
| X_tropicalis_ENSXETP00000016315 | paralogy | Xenopus |
| X_tropicalis_ENSXETP00000034890 | paralogy | Xenopus |
| X_tropicalis_ENSXETP00000057704 | paralogy | Xenopus |
| T_guttata_ENSTGUP00000010673 | paralogy | Zebra finch |
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Gene Ontology [+]
| GO id | Name | Ontology type | Evidence |
|---|---|---|---|
| GO:0007155 | cell adhesion | biological_proccess | IEA |
| GO:0005515 | protein binding | mollecular_function | IPI |
| GO:0005198 | structural molecule activity | mollecular_function | IEA |
| GO:0045296 | cadherin binding | mollecular_function | IEA |
| GO:0015629 | actin cytoskeleton | cell_component | IEA |
Check GO Evidence Codes here
Information from other databases [+]
- Gene info from FyBase [?] FBgn0003691
- Ensembl genome browser [?] : FBgn0003691
- Expression info from Arrayexpress [?] : FBgn0003691
- Protein expression from Protein Atlas: [?] FBgn0003691
Click on [?] for more information.
