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Gene Review

Xiap  -  X-linked inhibitor of apoptosis

Mus musculus

Synonyms: 1110015C02Rik, Aipa, Api3, Baculoviral IAP repeat-containing protein 4, Birc4, ...
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Disease relevance of Birc4

  • However, the interaction among XIAP, Smac/DIABLO, and caspases after in vivo cerebral ischemia is not well known [1].
  • Altogether, these data define a powerful survival function for XIAP and reinforce its possible role as a therapeutic target in human glioma cells.Gene Therapy (2007) 14, 147-161. doi:10.1038/; published online 7 September 2006 [2].
  • XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer [3].
  • We explored the expression of Smac/DIABLO, a newly identified mitochondrial apoptogenic molecule, and X-linked inhibitor of apoptosis protein (XIAP) in the brain subjected to ischemia/reperfusion [4].
  • When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset [5].

High impact information on Birc4

  • The c-IAP1 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death [6].
  • A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection [7].
  • Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth [8].
  • A novel role for XIAP in copper homeostasis through regulation of MURR1 [9].
  • XIAP is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases [9].

Chemical compound and disease context of Birc4


Biological context of Birc4

  • Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice [2].
  • XIAP inhibits the caspase reaction via binding to caspases, and is inhibited via binding to the second mitochondria-derived activator of caspase (Smac)/DIABLO to tightly control apoptotic cell death [1].
  • Northern blot analysis reveals an 8-kb miap-3 transcript in all tissues examined to date. miap-3 is composed of six exons and five introns spanning approximately 20 kb. miap-3 has been assigned to the A3-A5 region of mouse chromosome X by FISH analysis [11].
  • Results from 3-(4,5-methylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and clonogenic assays suggest that inhibition of survivin or XIAP greatly decreased cell survival following irradiation [3].
  • This suggests that there exists a compensatory mechanism that leads to upregulation of other family members when XIAP expression is lost [12].

Anatomical context of Birc4

  • In contrast, non-neoplastic SV-FHAS human astrocytes and other non-neoplastic cells express XIAP at very low levels and resist these effects of adenovirus-expressing XIAP antisense RNA (Ad-XIAP-as) [2].
  • In situ hybridization showed that the expression of XIAP was remarkably reduced in the motor neurons of Tg mice, and the expression of cIAP-1 was strongly increased in the reactive astrocytes of Tg mice [13].
  • XIAP-deficiency leads to delayed lobuloalveolar development in the mammary gland [14].
  • Conversely, adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia [15].
  • To study the role of this, we generated double transgenic mice expressing XIAP in ALS spinal cord neurons using the Thy1 promoter [16].

Associations of Birc4 with chemical compounds

  • Sequential treatment with SN-38 followed by flavopiridol was associated with higher activation of caspase-3 and greater cleavage of both p21 and XIAP, an inhibitor of apoptosis, compared with other treatment schedules [17].
  • These results suggest that the ability of cisplatin to down-regulate Xiap content may be an important determinant of chemosensitivity in hOSE cancer [18].
  • Furthermore, NSE-xiap mice treated with MPTP did not exhibit deficits in exploratory behaviour in an open-field test [19].
  • We demonstrate that nigrostriatal dopamine neurons of NSE-xiap mice were resistant to the damaging effects of the dopaminergic neurotoxin MPTP [19].
  • Finally, elevated expression of X-linked inhibitor of apoptosis, XIAP, was observed in thymi from DEX-treated PRL -/-Graft mice [20].

Regulatory relationships of Birc4

  • In contrast, the neuronal competence pathway permitted cytochrome c to activate caspases by inducing a marked reduction in XIAP levels in these neurons [21].

Other interactions of Birc4


Analytical, diagnostic and therapeutic context of Birc4


  1. Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia. Saito, A., Hayashi, T., Okuno, S., Ferrand-Drake, M., Chan, P.H. J. Cereb. Blood Flow Metab. (2003) [Pubmed]
  2. Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice. Naumann, U., B??hr, O., Wolburg, H., Altenberend, S., Wick, W., Liston, P., Ashkenazi, A., Weller, M. Gene Ther. (2007) [Pubmed]
  3. XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Cao, C., Mu, Y., Hallahan, D.E., Lu, B. Oncogene (2004) [Pubmed]
  4. Subcellular localization of a promoter and an inhibitor of apoptosis (Smac/DIABLO and XIAP) during brain ischemia/reperfusion. Shibata, M., Hattori, H., Sasaki, T., Gotoh, J., Hamada, J., Fukuuchi, Y. Neuroreport (2002) [Pubmed]
  5. The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. Inoue, H., Tsukita, K., Iwasato, T., Suzuki, Y., Tomioka, M., Tateno, M., Nagao, M., Kawata, A., Saido, T.C., Miura, M., Misawa, H., Itohara, S., Takahashi, R. EMBO J. (2003) [Pubmed]
  6. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Yang, Y., Fang, S., Jensen, J.P., Weissman, A.M., Ashwell, J.D. Science (2000) [Pubmed]
  7. A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection. Holcik, M., Lefebvre, C., Yeh, C., Chow, T., Korneluk, R.G. Nat. Cell Biol. (1999) [Pubmed]
  8. Pin1 interacts with a specific serine-proline motif of hepatitis B virus x-protein to enhance hepatocarcinogenesis. Pang, R., Lee, T.K., Poon, R.T., Fan, S.T., Wong, K.B., Kwong, Y.L., Tse, E. Gastroenterology (2007) [Pubmed]
  9. A novel role for XIAP in copper homeostasis through regulation of MURR1. Burstein, E., Ganesh, L., Dick, R.D., van De Sluis, B., Wilkinson, J.C., Klomp, L.W., Wijmenga, C., Brewer, G.J., Nabel, G.J., Duckett, C.S. EMBO J. (2004) [Pubmed]
  10. FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. Lee, T.K., Man, K., Ho, J.W., Sun, C.K., Ng, K.T., Wang, X.H., Wong, Y.C., Ng, I.O., Xu, R., Fan, S.T. Carcinogenesis (2004) [Pubmed]
  11. Genomic organization and primary characterization of miap-3: the murine homologue of human X-linked IAP. Farahani, R., Fong, W.G., Korneluk, R.G., MacKenzie, A.E. Genomics (1997) [Pubmed]
  12. Characterization of XIAP-deficient mice. Harlin, H., Reffey, S.B., Duckett, C.S., Lindsten, T., Thompson, C.B. Mol. Cell. Biol. (2001) [Pubmed]
  13. X-Linked inhibitor of apoptosis protein is involved in mutant SOD1-mediated neuronal degeneration. Ishigaki, S., Liang, Y., Yamamoto, M., Niwa, J., Ando, Y., Yoshihara, T., Takeuchi, H., Doyu, M., Sobue, G. J. Neurochem. (2002) [Pubmed]
  14. XIAP-deficiency leads to delayed lobuloalveolar development in the mammary gland. Olayioye, M.A., Kaufmann, H., Pakusch, M., Vaux, D.L., Lindeman, G.J., Visvader, J.E. Cell Death Differ. (2005) [Pubmed]
  15. Neuroprotection by the inhibition of apoptosis. Robertson, G.S., Crocker, S.J., Nicholson, D.W., Schulz, J.B. Brain Pathol. (2000) [Pubmed]
  16. XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice. Wootz, H., Hansson, I., Korhonen, L., Lindholm, D. Exp. Cell Res. (2006) [Pubmed]
  17. Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. Motwani, M., Jung, C., Sirotnak, F.M., She, Y., Shah, M.A., Gonen, M., Schwartz, G.K. Clin. Cancer Res. (2001) [Pubmed]
  18. Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Li, J., Feng, Q., Kim, J.M., Schneiderman, D., Liston, P., Li, M., Vanderhyden, B., Faught, W., Fung, M.F., Senterman, M., Korneluk, R.G., Tsang, B.K. Endocrinology (2001) [Pubmed]
  19. Attenuation of MPTP-induced neurotoxicity and behavioural impairment in NSE-XIAP transgenic mice. Crocker, S.J., Liston, P., Anisman, H., Lee, C.J., Smith, P.D., Earl, N., Thompson, C.S., Park, D.S., Korneluk, R.G., Robertson, G.S. Neurobiol. Dis. (2003) [Pubmed]
  20. Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. Krishnan, N., Thellin, O., Buckley, D.J., Horseman, N.D., Buckley, A.R. Endocrinology (2003) [Pubmed]
  21. Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. Potts, P.R., Singh, S., Knezek, M., Thompson, C.B., Deshmukh, M. J. Cell Biol. (2003) [Pubmed]
  22. The Sept4 septin locus is required for sperm terminal differentiation in mice. Kissel, H., Georgescu, M.M., Larisch, S., Manova, K., Hunnicutt, G.R., Steller, H. Dev. Cell (2005) [Pubmed]
  23. BRCA1 phosphorylation regulates caspase-3 activation in UV-induced apoptosis. Martin, S.A., Ouchi, T. Cancer Res. (2005) [Pubmed]
  24. Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia. Trapp, T., Korhonen, L., Besselmann, M., Martinez, R., Mercer, E.A., Lindholm, D. Mol. Cell. Neurosci. (2003) [Pubmed]
  25. IAP survivin regulates atherosclerotic macrophage survival. Blanc-Brude, O.P., Teissier, E., Castier, Y., Lesèche, G., Bijnens, A.P., Daemen, M., Staels, B., Mallat, Z., Tedgui, A. Arterioscler. Thromb. Vasc. Biol. (2007) [Pubmed]
  26. Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. Karikari, C.A., Roy, I., Tryggestad, E., Feldmann, G., Pinilla, C., Welsh, K., Reed, J.C., Armour, E.P., Wong, J., Herman, J., Rakheja, D., Maitra, A. Mol. Cancer Ther. (2007) [Pubmed]
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