X連鎖ア・トーシス抑制タンパク質

関: X-linked inhibitor of apoptosis protein

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/10/18 20:33:52」(JST)

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X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC), is a protein that stops apoptotic cell death. In human, this protein (XIAP) is produced by a gene named XIAP gene located on the X chromosome.^[1]^[2]

XIAP is a member of the inhibitor of apoptosis family of proteins (IAP). IAPs were initially identified in baculoviruses, but XIAP is one of the homologous proteins found in mammals.^[3] It is so called because it was first discovered by a 273 base pair site on the X chromosome.^[1] The protein is also called human IAP-like Protein (hILP), because it is not as well conserved as the human IAPS: hIAP-1 and hIAP-2.^[1]^[4] XIAP is the most potent human IAP protein currently identified.^[5]

Discovery

Neuronal apoptosis inhibitor protein (NAIP) was the first homolog to baculoviral IAPs that was identified in humans.^[1] With the sequencing data of NIAP, the gene sequence for a RING zinc-finger domain was discovered at site Xq24-25.^[1] Using PCR and cloning, three BIR domains and a RING finger were found on the protein, which became known as X-linked Inhibitor of Apoptosis Protein. The transcript size of Xiap is 9.0kb, with an open reading frame of 1.8kb.^[1] Xiap mRNA has been observed in all human adult and fetal tissues "except peripheral blood leukocytes".^[1] The XIAP sequences led to the discovery of other members of the IAP family.

Structure

XIAP consists of three major types of structural elements (domains). Firstly, there is the baculoviral IAP repeat (BIR) domain consisting of approximately 70 amino acids, which characterizes all IAP.^[5] Secondly, there is a UBA domain, which allows XIAP to bind to ubiquitin. Thirdly, there is a zinc-binding domain, or a “carboxy-terminal RING Finger”.^[4] XIAP has been characterized with three amino-terminal BIR domains followed by one UBA domain and finally one RING domain.^[6] Between the BIR-1 and BIR-2 domains, there is a linker-BIR-2 region that is thought to contain the only element that comes into contact with the caspase molecule to form the XIAP/Caspase-7 complex.^[7]

Function

XIAP stops apoptotic cell death that is induced either by viral infection or by overproduction of caspases. caspases are the enzymes primarily responsible for cell death.^[4] XIAP binds to and inhibits caspase 3, 7 and 9.^[5] The BIR2 domain of XIAP inhibits caspase 3 and 7, while BIR3 binds to and inhibits caspase 9.^[5] The RING domain utilizes E3 ubiquitin ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via proteasome activity.^[8] However, mutations affecting the RING Finger do not significantly affect apoptosis, indicating that the BIR domain is sufficient for the protein’s function.^[4] When inhibiting caspase-3 and caspase-7 activity, the BIR2 domain of XIAP binds to the active-site substrate groove, blocking access of the normal protein substrate that would result in apoptosis.^[8]^[9]

Caspases are activated by cytochrome c, which is released into the cytosol by dysfunctioning mitochondria.^[4] Studies show that XIAP does not directly affect cytochrome c.^[4]

XIAP distinguishes itself from the other human IAPs because it is able to effectively prevent cell death due to "TNF-α, Fas, UV light, and genotoxic agents".^[4]

The second BIR domain of XIAP can be shown binding to caspase 3 where a protein substrate would normally bind during aptosis. By blocking this binding, XIAP inhibits apoptosis.

Inhibiting XIAP

XIAP is inhibited by DIABLO (Smac) and HTRA2 (Omi), two death-signaling proteins released into the cytoplasm by the mitochondria.^[6] Smac/DIABLO, a mitochondrial protein and negative regulator of XIAP, can enhance apoptosis by binding to XIAP and preventing it from binding to caspases. This allows normal caspase activity to proceed. The binding process of Smac/DIABLO to XIAP and caspase release requires a conserved tetrapeptide motif.^[8]

Clinical significance

Deregulation of XIAP can result in “cancer, neurodegenerative disorders, and autoimmunity”.^[6] High proportions of XIAP may function as a tumor marker.^[5] In the development of lung cancer NCI-H460, the overexpression of XIAP not only inhibits caspase, but also stops the activity of cytochrome c (Apoptosis). In developing prostate cancer, XIAP is one of four IAPs overexpressed in the prostatic epithelium, indicating that a molecule that inhibits all IAPs may be necessary for effective treatment.^[10] Apoptotic regulation is an extremely important biological function, as evidenced by "the conservation of the IAPs from humans to Drosophila".^[1]

Mutations in the XIAP gene can result in a severe and rare type of inflammatory bowel disease.^[11] Defects in the XIAP gene can also result in an extremely rare condition called X-linked lymphoproliferative disease.^[11]

Interactions

XIAP has been shown to interact with:

ALS2CR2,^[12]
Caspase 3.^[13]^[14]^[15]^[16]^[17]^[18]
Caspase 7,^[13]^[14]^[15]^[16]
Caspase-9,^[19]^[20]^[21]^[22]
Diablo homolog^[20]^[23]^[24]^[25]^[26]
HtrA serine peptidase 2,^[23]^[27]
MAGED1,^[28]
MAP3K2,^[29]
MAP3K7IP1,^[12]^[30] and
XAF1.^[31]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG (January 1996). "Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes". Nature 379 (6563): 349–53. doi:10.1038/379349a0. PMID 8552191.
^ Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB (June 1996). "A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors". EMBO J. 15 (11): 2685–94. PMC 450204. PMID 8654366. //www.ncbi.nlm.nih.gov/pmc/articles/PMC450204/.
^ Holcik M, Korneluk RG (July 2000). "Functional Characterization of the X-Linked Inhibitor of Apoptosis (XIAP) Internal Ribosome Entry Site Element: Role of La Autoantigen in XIAP Translation". Mol. Cell. Biol. 20 (13): 4648–57. doi:10.1128/MCB.20.13.4648-4657.2000. PMC 85872. PMID 10848591. //www.ncbi.nlm.nih.gov/pmc/articles/PMC85872/.
^ ^a ^b ^c ^d ^e ^f ^g Duckett CS, Li F, Wang Y, Tomaselli KJ, Thompson CB, Armstrong RC (1 January 1998). "Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c". Mol. Cell. Biol. 18 (1): 608–15. PMC 121528. PMID 9418907. http://mcb.asm.org/cgi/content/abstract/18/1/608.
^ ^a ^b ^c ^d ^e Deveraux QL, Reed JC (February 1999). "IAP family proteins – suppressors of apoptosis". Genes Dev. 13 (3): 239–52. doi:10.1101/gad.13.3.239. PMID 9990849.
^ ^a ^b ^c Wilkinson JC, Cepero E, Boise LH, Duckett CS (August 2004). "Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis". Mol. Cell. Biol. 24 (16): 7003–14. doi:10.1128/MCB.24.16.7003-7014.2004. PMC 479745. PMID 15282301. //www.ncbi.nlm.nih.gov/pmc/articles/PMC479745/.
^ Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H (March 2001). "Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain". Cell 104 (5): 781–90. doi:10.1016/S0092-8674(01)00273-2. PMID 11257231.
^ ^a ^b ^c Gewies A (2003). "Introduction to Apoptosis". CellDeath.de. http://www.celldeath.de/encyclo/aporev/apointro.pdf. Retrieved 2008-08-12.
^ Eckelman BP, Salvesen GS, Scott FL (October 2006). "Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family". EMBO Rep. 7 (10): 988–94. doi:10.1038/sj.embor.7400795. PMC 1618369. PMID 17016456. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1618369/.
^ Watson RW, Fitzpatrick JM (December 2005). "Targeting apoptosis in prostate cancer: focus on caspases and inhibitors of apoptosis proteins". BJU Int. 96 Suppl 2: 30–4. doi:10.1111/j.1464-410X.2005.05944.x. PMID 16359436.
^ ^a ^b Worthey EA, Mayer AN, Syverson GD, et al. (December 2011). "Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease". Genet Med 13 (1): 255–62. doi:10.1097/GIM.0b013e3182088158. PMID 21173700. http://journals.lww.com/geneticsinmedicine/Documents/GIM200819_Revised.pdf. Lay summary – Milwaukee Journal.
^ ^a ^b Sanna MG, da Silva Correia J, Luo Y, Chuang B, Paulson LM, Nguyen B, Deveraux QL, Ulevitch RJ (August 2002). "ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis". J. Biol. Chem. 277 (34): 30454–62. doi:10.1074/jbc.M203312200. PMID 12048196.
^ ^a ^b Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS (March 2001). "Structural basis for the inhibition of caspase-3 by XIAP". Cell 104 (5): 791–800. doi:10.1016/S0092-8674(01)00274-4. PMID 11257232.
^ ^a ^b Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (December 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. PMC 1170295. PMID 9384571. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1170295/.
^ ^a ^b Deveraux QL, Takahashi R, Salvesen GS, Reed JC (July 1997). "X-linked IAP is a direct inhibitor of cell-death proteases". Nature 388 (6639): 300–4. doi:10.1038/40901. PMID 9230442.
^ ^a ^b Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R (July 2001). "X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes". J. Biol. Chem. 276 (29): 27058–63. doi:10.1074/jbc.M102415200. PMID 11359776.
^ Suzuki Y, Nakabayashi Y, Takahashi R (July 2001). "Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death". Proc. Natl. Acad. Sci. U.S.A. 98 (15): 8662–7. doi:10.1073/pnas.161506698. PMC 37492. PMID 11447297. //www.ncbi.nlm.nih.gov/pmc/articles/PMC37492/.
^ Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL (April 2002). "The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3– and caspase 9–interacting sites". J. Cell Biol. 157 (1): 115–24. doi:10.1083/jcb.200108085. PMC 2173256. PMID 11927604. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2173256/.
^ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
^ ^a ^b Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE (September 2004). "Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9". J. Biol. Chem. 279 (39): 40622–8. doi:10.1074/jbc.M405963200. PMID 15280366.
^ Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (April 1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. 17 (8): 2215–23. doi:10.1093/emboj/17.8.2215. PMC 1170566. PMID 9545235. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1170566/.
^ Richter BW, Mir SS, Eiben LJ, Lewis J, Reffey SB, Frattini A, Tian L, Frank S, Youle RJ, Nelson DL, Notarangelo LD, Vezzoni P, Fearnhead HO, Duckett CS (July 2001). "Molecular Cloning of ILP-2, a Novel Member of the Inhibitor of Apoptosis Protein Family". Mol. Cell. Biol. 21 (13): 4292–301. doi:10.1128/MCB.21.13.4292-4301.2001. PMC 87089. PMID 11390657. //www.ncbi.nlm.nih.gov/pmc/articles/PMC87089/.
^ ^a ^b Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (January 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". J. Biol. Chem. 277 (1): 445–54. doi:10.1074/jbc.M109891200. PMID 11604410.
^ Hunter AM, Kottachchi D, Lewis J, Duckett CS, Korneluk RG, Liston P (February 2003). "A novel ubiquitin fusion system bypasses the mitochondria and generates biologically active Smac/DIABLO". J. Biol. Chem. 278 (9): 7494–9. doi:10.1074/jbc.C200695200. PMID 12511567.
^ Song Z, Yao X, Wu M (June 2003). "Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis". J. Biol. Chem. 278 (25): 23130–40. doi:10.1074/jbc.M300957200. PMID 12660240.
^ Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (July 2000). "Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins". Cell 102 (1): 43–53. doi:10.1016/S0092-8674(00)00009-X. PMID 10929712.
^ Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES (October 2003). "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein". J. Biol. Chem. 278 (40): 38699–706. doi:10.1074/jbc.M303179200. PMID 12865429.
^ Jordan BW, Dinev D, LeMellay V, Troppmair J, Gotz R, Wixler L, Sendtner M, Ludwig S, Rapp UR (October 2001). "Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death". J. Biol. Chem. 276 (43): 39985–9. doi:10.1074/jbc.C100171200. PMID 11546791.
^ Winsauer G, Resch U, Hofer-Warbinek R, Schichl YM, de Martin R (November 2008). "XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2". Cell. Signal. 20 (11): 2107–12. doi:10.1016/j.cellsig.2008.08.004. PMID 18761086.
^ Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K (January 1999). "XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway". EMBO J. 18 (1): 179–87. doi:10.1093/emboj/18.1.179. PMC 1171113. PMID 9878061. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1171113/.
^ Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG (February 2001). "Identification of XAF1 as an antagonist of XIAP anti-Caspase activity". Nat. Cell Biol. 3 (2): 128–33. doi:10.1038/35055027. PMID 11175744.

External links

GeneReviews/NCBI/NIH/UW entry on Lymphoproliferative Disease, X-Linked

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. X連鎖リンパ増殖性疾患 x linked lymphoproliferative disease
2. 血球貪食性リンパ組織球症（HLH） hemophagocytic lymphohistiocytosis
3. 複合免疫不全 combined immunodeficiencies
4. 原発性免疫不全症の診断のためのフローサイトメトリー flow cytometry for the diagnosis of primary immunodeficiencies
5. エプスタインバーウイルス（EBウイルス）感染の臨床的特徴および治療 clinical manifestations and treatment of epstein barr virus infection

English Journal

UVB-induced anti-survival and pro-apoptotic effects on HaCaT human keratinocytes via caspase- and PKC-dependent downregulation of PKB, HIAP-1, Mcl-1, XIAP and ER stress.

Park YK, Jang BC.Author information Department of Molecular Medicine, College of Medicine, Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.AbstractEvidence suggests that solar ultraviolet B (UVB) radiation inhibits growth and/or induces apoptosis of human skin cells. However, mechanisms underlying the UVB-induced anti-survival and pro-apoptotic effects on human skin cells remain unclear. In this study, we investigated the effect of UVB radiation on survival and apoptosis of HaCaT human keratinocytes and determined possible molecular, cellular and signaling mechanisms including cross-regulation, which are responsible for the UVB's anti-survival and/or pro-apoptotic effects. The results showed that UVB radiation at 400 mJ/cm2 for 8 h largely decreased cell survival and induced DNA fragmentation, an index of apoptosis, in HaCaT human keratinocytes. On a mechanistic level, UVB radiation triggered the activation of caspase-9, cleavage of poly(ADP‑ribose) polymerase, and downregulation of myeloid cell leukemia-1 (Mcl-1), human inhibitor of apoptosis protein-1 (HIAP-1), X-linked IAP (XIAP), and protein kinase B (PKB), but did not affect the expression of B-cell lymphoma-2 in HaCaT cells. UVB radiation also upregulated the expression of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) stress marker, in HaCaT cells. Of note, results of pharmacological inhibition studies have demonstrated that pretreatment with z-VAD-fmk, a pan‑caspase inhibitor strongly attenuated UVB-induced apoptosis, the activation of caspase-9, downregulation of Mcl-1, XIAP and PKB (but not HIAP-1), and upregulation of GRP78, while pretreatment with GF109203 or GO6983, pan-PKC inhibitors, substantially blocked the UVB-induced reduction of cell survival, activation of caspase-9, downregulation of HIAP-1, XIAP, and PKB (but not Mcl-1), and GRP78 upregulation in HaCaT cells. Collectively, these results demonstrated that UVB has strong anti-survival and pro-apoptotic effects on HaCaT cells and the effects were largely mediated via the activation of caspase-9 and protein kinase Cs, which subsequently downregulated PKB, XIAP, HIAP-1 and Mcl-1, and triggered ER stress.
International journal of molecular medicine.Int J Mol Med.2014 Mar;33(3):695-702. doi: 10.3892/ijmm.2013.1595. Epub 2013 Dec 19.
Evidence suggests that solar ultraviolet B (UVB) radiation inhibits growth and/or induces apoptosis of human skin cells. However, mechanisms underlying the UVB-induced anti-survival and pro-apoptotic effects on human skin cells remain unclear. In this study, we investigated the effect of UVB radiat
PMID 24356997

Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services.

Roberts JL1, Hovanes K2, Dasouki M3, Manzardo AM1, Butler MG4.Author information 1Departments of Psychiatry, Behavioral Sciences and Pediatrics, The University of Kansas, Medical Center, Kansas City, KS, USA.2CombiMatrix Diagnostics, Irvine, CA, USA.3Department of Neurology, The University of Kansas Medical Center, Kansas City, KS, USA; King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.4Departments of Psychiatry, Behavioral Sciences and Pediatrics, The University of Kansas, Medical Center, Kansas City, KS, USA. Electronic address: mbutler4@kumc.edu.AbstractChromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.
Gene.Gene.2014 Feb 1;535(1):70-8. doi: 10.1016/j.gene.2013.10.020. Epub 2013 Nov 2.
Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum dis
PMID 24188901

Acacetin (5,7-dihydroxy-4'-methoxyflavone) exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signaling in prostate cancer cells.

Kim HR1, Park CG2, Jung JY1.Author information 1Department of Companion and Laboratory Animal Science, Kongju National University, Yesan 340-702, Republic of Korea.2Department of Rural Construction Engineering, Kongju National University, Yesan 340-702, Republic of Korea.AbstractAcacetin (5,7-dihydroxy-4'-methoxyflavone) is a flavonoid compound with antimutagenic, antiplasmodial, antiperoxidant, anti-inflammatory and anticancer effects. However, the molecular targets and pathways underlying the anticancer effects of acacetin are yet to be elucidated. In this study, we investigated whether acacetin induces apoptosis in the human prostate cancer cell line, DU145. The results of 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays revealed that cell viability decreased in a dose- and time-dependent manner in response to acacetin. 4',6-Diamidino-2-phenylindole (DAPI) staining revealed that chromatin condensation significantly increased in a dose-dependent manner. Flow cytometric analysis indicated that acacetin suppressed the viability of DU145 cells by inducing apoptosis. Western blot anlaysis of various markers of signaling pathways revealed that acacetin targets the Akt and nuclear factor (NF)-κB signaling pathways by inhibiting the phosphorylation of IκBα and NF-κB in a dose-dependent manner. Consistent with its ability to induce apoptosis, the acacetin-mediated inhibition of the pro-survival pathway, Akt, and of the NF-κB pathway was accompanied by a marked reduction in the levels of the NF-κB‑regulated anti-apoptotic proteins, Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP), as well as of the proliferative protein, cyclooxygenase (COX)-2. We further evaluated the effects of acacetin on prostate cancer using mice subcutaneously injected with DU145 prostate cancer cells. The acacetin-treated nude mice bearing DU145 tumor xenografts exhibited significantly reduced tumor size and weight, due to the effects of acacetin on cancer cell apoptosis, as determined by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assay. Our findings suggest that acacetin exerts antitumor effects by targeting the Akt/NF-κB signaling pathway. Rurther investigations on this flavonoid are warranted to evaluate its potential use in the prevention and therapy of prostate cancer.
International journal of molecular medicine.Int J Mol Med.2014 Feb;33(2):317-24. doi: 10.3892/ijmm.2013.1571. Epub 2013 Nov 27.
Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a flavonoid compound with antimutagenic, antiplasmodial, antiperoxidant, anti-inflammatory and anticancer effects. However, the molecular targets and pathways underlying the anticancer effects of acacetin are yet to be elucidated. In this study, we inves
PMID 24285354

Japanese Journal

A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral blood containing gastric cancer-derived circulating tumor cells

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 18(4), 751-761, 2015
NAID 40020631484

X連鎖リンパ増殖症候群 (増大号特集小児血液疾患 : よくわかる最新知見) -- (リンパ球疾患)

小児科 55(11), 1639-1644, 2014-10
NAID 40020239038

P2-56-4 XIAPは卵巣明細胞腺癌の治療targetになりうる(Group 94 卵巣腫瘍・基礎5,一般演題,公益社団法人日本産科婦人科学会第66回学術講演会)

日本産科婦人科學會雜誌 66(2), 744, 2014-02-01
NAID 110009812452

Related Pictures

Figure 2. protein where the XIAP mutation occurs XIAP, AVI-tagged(Human),Recombinant Human Esquema de la apoptosis. Como véis, un Caspase 7 of X-linked inhibitor of apoptosis (XIAP XIAP. By eliminating the function of XIAP Immunofluorescence-XIAP antibody(ab21278

★リンクテーブル★

リンク元	「X-linked inhibitor of apoptosis protein」「X連鎖アポトーシス抑制タンパク質」

「X-linked inhibitor of apoptosis protein」

X-linked inhibitor of apoptosis
	; PDB rendering based on 1c9q.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1C9Q, 1F9X, 1G3F, 1G73, 1I3O, 1I4O, 1I51, 1KMC, 1NW9, 1TFQ, 1TFT, 2ECG, 2JK7, 2KNA, 2OPY, 2OPZ, 2POI, 2POP, 2QRA, 2VSL, 3CLX, 3CM2, 3CM7, 3EYL, 3G76, 3HL5, 3UW4, 3UW5
Identifiers
Symbols	XIAP; API3; BIRC4; IAP-3; ILP1; MIHA; XLP2; hIAP-3; hIAP3
External IDs	OMIM: 300079 MGI: 107572 HomoloGene: 901 ChEMBL: 4198 GeneCards: XIAP Gene
EC number	6.3.2.-
Gene Ontology
Molecular function	• ubiquitin-protein ligase activity; • protein binding; • zinc ion binding; • cysteine-type endopeptidase inhibitor activity involved in apoptotic process;
Cellular component	• nucleus; • cytoplasm; • cytosol;
Biological process	• apoptotic process; • anti-apoptosis; • response to DNA damage stimulus; • Wnt receptor signaling pathway; • regulation of BMP signaling pathway; • regulation of cell proliferation; • negative regulation of apoptotic process; • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; • regulation of innate immune response; • regulation of inflammatory response; • copper ion homeostasis; • regulation of nucleotide-binding oligomerization domain containing signaling pathway; • positive regulation of canonical Wnt receptor signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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　　[★] X連鎖アポトーシス抑制タンパク質

関: XIAP

抗アポトーシス因子

「X連鎖アポトーシス抑制タンパク質」

　　[★]

英: X-linked inhibitor of apoptosis protein、XIAP

[Liston-0] ^ ^a ^b ^c ^d ^e ^f ^g ^h Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG (January 1996). "Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes". Nature 379 (6563): 349–53. doi:10.1038/379349a0. PMID 8552191.

[pmid8654366-1] Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB (June 1996). "A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors". EMBO J. 15 (11): 2685–94. PMC 450204. PMID 8654366. //www.ncbi.nlm.nih.gov/pmc/articles/PMC450204/.

[Holcik-2] Holcik M, Korneluk RG (July 2000). "Functional Characterization of the X-Linked Inhibitor of Apoptosis (XIAP) Internal Ribosome Entry Site Element: Role of La Autoantigen in XIAP Translation". Mol. Cell. Biol. 20 (13): 4648–57. doi:10.1128/MCB.20.13.4648-4657.2000. PMC 85872. PMID 10848591. //www.ncbi.nlm.nih.gov/pmc/articles/PMC85872/.

[Duckett-3] ^ ^a ^b ^c ^d ^e ^f ^g Duckett CS, Li F, Wang Y, Tomaselli KJ, Thompson CB, Armstrong RC (1 January 1998). "Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c". Mol. Cell. Biol. 18 (1): 608–15. PMC 121528. PMID 9418907. http://mcb.asm.org/cgi/content/abstract/18/1/608.

[Reed-4] Deveraux QL, Reed JC (February 1999). "IAP family proteins – suppressors of apoptosis". Genes Dev. 13 (3): 239–52. doi:10.1101/gad.13.3.239. PMID 9990849.

[Wilkinson-5] Wilkinson JC, Cepero E, Boise LH, Duckett CS (August 2004). "Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis". Mol. Cell. Biol. 24 (16): 7003–14. doi:10.1128/MCB.24.16.7003-7014.2004. PMC 479745. PMID 15282301. //www.ncbi.nlm.nih.gov/pmc/articles/PMC479745/.

[pmid11257231-6] Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H (March 2001). "Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain". Cell 104 (5): 781–90. doi:10.1016/S0092-8674(01)00273-2. PMID 11257231.

[Gewies-7] Gewies A (2003). "Introduction to Apoptosis". CellDeath.de. http://www.celldeath.de/encyclo/aporev/apointro.pdf. Retrieved 2008-08-12.

[pmid17016456-8] Eckelman BP, Salvesen GS, Scott FL (October 2006). "Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family". EMBO Rep. 7 (10): 988–94. doi:10.1038/sj.embor.7400795. PMC 1618369. PMID 17016456. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1618369/.

[Watson-9] Watson RW, Fitzpatrick JM (December 2005). "Targeting apoptosis in prostate cancer: focus on caspases and inhibitors of apoptosis proteins". BJU Int. 96 Suppl 2: 30–4. doi:10.1111/j.1464-410X.2005.05944.x. PMID 16359436.

[Worthey_2011-10] Worthey EA, Mayer AN, Syverson GD, et al. (December 2011). "Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease". Genet Med 13 (1): 255–62. doi:10.1097/GIM.0b013e3182088158. PMID 21173700. http://journals.lww.com/geneticsinmedicine/Documents/GIM200819_Revised.pdf. Lay summary – Milwaukee Journal.

[pmid12048196-11] Sanna MG, da Silva Correia J, Luo Y, Chuang B, Paulson LM, Nguyen B, Deveraux QL, Ulevitch RJ (August 2002). "ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis". J. Biol. Chem. 277 (34): 30454–62. doi:10.1074/jbc.M203312200. PMID 12048196.

[pmid11257232-12] Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS (March 2001). "Structural basis for the inhibition of caspase-3 by XIAP". Cell 104 (5): 791–800. doi:10.1016/S0092-8674(01)00274-4. PMID 11257232.

[pmid9384571-13] Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (December 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. PMC 1170295. PMID 9384571. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1170295/.

[pmid9230442-14] Deveraux QL, Takahashi R, Salvesen GS, Reed JC (July 1997). "X-linked IAP is a direct inhibitor of cell-death proteases". Nature 388 (6639): 300–4. doi:10.1038/40901. PMID 9230442.

[pmid11359776-15] Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R (July 2001). "X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes". J. Biol. Chem. 276 (29): 27058–63. doi:10.1074/jbc.M102415200. PMID 11359776.

[pmid11447297-16] Suzuki Y, Nakabayashi Y, Takahashi R (July 2001). "Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death". Proc. Natl. Acad. Sci. U.S.A. 98 (15): 8662–7. doi:10.1073/pnas.161506698. PMC 37492. PMID 11447297. //www.ncbi.nlm.nih.gov/pmc/articles/PMC37492/.

[pmid11927604-17] Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL (April 2002). "The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3– and caspase 9–interacting sites". J. Cell Biol. 157 (1): 115–24. doi:10.1083/jcb.200108085. PMC 2173256. PMID 11927604. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2173256/.

[pmid16189514-18] Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.

[pmid15280366-19] Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE (September 2004). "Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9". J. Biol. Chem. 279 (39): 40622–8. doi:10.1074/jbc.M405963200. PMID 15280366.

[pmid9545235-20] Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (April 1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. 17 (8): 2215–23. doi:10.1093/emboj/17.8.2215. PMC 1170566. PMID 9545235. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1170566/.

[pmid11390657-21] Richter BW, Mir SS, Eiben LJ, Lewis J, Reffey SB, Frattini A, Tian L, Frank S, Youle RJ, Nelson DL, Notarangelo LD, Vezzoni P, Fearnhead HO, Duckett CS (July 2001). "Molecular Cloning of ILP-2, a Novel Member of the Inhibitor of Apoptosis Protein Family". Mol. Cell. Biol. 21 (13): 4292–301. doi:10.1128/MCB.21.13.4292-4301.2001. PMC 87089. PMID 11390657. //www.ncbi.nlm.nih.gov/pmc/articles/PMC87089/.

[pmid11604410-22] Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (January 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". J. Biol. Chem. 277 (1): 445–54. doi:10.1074/jbc.M109891200. PMID 11604410.

[pmid12511567-23] Hunter AM, Kottachchi D, Lewis J, Duckett CS, Korneluk RG, Liston P (February 2003). "A novel ubiquitin fusion system bypasses the mitochondria and generates biologically active Smac/DIABLO". J. Biol. Chem. 278 (9): 7494–9. doi:10.1074/jbc.C200695200. PMID 12511567.

[pmid12660240-24] Song Z, Yao X, Wu M (June 2003). "Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis". J. Biol. Chem. 278 (25): 23130–40. doi:10.1074/jbc.M300957200. PMID 12660240.

[pmid10929712-25] Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (July 2000). "Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins". Cell 102 (1): 43–53. doi:10.1016/S0092-8674(00)00009-X. PMID 10929712.

[pmid12865429-26] Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES (October 2003). "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein". J. Biol. Chem. 278 (40): 38699–706. doi:10.1074/jbc.M303179200. PMID 12865429.

[pmid11546791-27] Jordan BW, Dinev D, LeMellay V, Troppmair J, Gotz R, Wixler L, Sendtner M, Ludwig S, Rapp UR (October 2001). "Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death". J. Biol. Chem. 276 (43): 39985–9. doi:10.1074/jbc.C100171200. PMID 11546791.

[pmid18761086-28] Winsauer G, Resch U, Hofer-Warbinek R, Schichl YM, de Martin R (November 2008). "XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2". Cell. Signal. 20 (11): 2107–12. doi:10.1016/j.cellsig.2008.08.004. PMID 18761086.

[pmid9878061-29] Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K (January 1999). "XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway". EMBO J. 18 (1): 179–87. doi:10.1093/emboj/18.1.179. PMC 1171113. PMID 9878061. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1171113/.

[pmid11175744-30] Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG (February 2001). "Identification of XAF1 as an antagonist of XIAP anti-Caspase activity". Nat. Cell Biol. 3 (2): 128–33. doi:10.1038/35055027. PMID 11175744.

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XIAP