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Gene Review

DIABLO  -  diablo, IAP-binding mitochondrial protein

Homo sapiens

Synonyms: DFNA64, DIABLO-S, Diablo homolog, mitochondrial, Direct IAP-binding protein with low pI, FLJ10537, ...
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Disease relevance of DIABLO


Psychiatry related information on DIABLO

  • In addition, this may be particularly relevant in Alzheimer's disease since the caspase-generated C31 peptide, an established cytotoxin, acquires Smac/Diablo-like properties after apoptotic processing [5].

High impact information on DIABLO

  • Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins [6].
  • Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition [7].
  • We report here the identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway [7].
  • Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo [8].
  • Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3 [9].

Chemical compound and disease context of DIABLO


Biological context of DIABLO


Anatomical context of DIABLO


Associations of DIABLO with chemical compounds

  • Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 nM flavopiridol and 300 nM MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c, Smac/DIABLO release, loss of deltaPsi(m)), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential [22].
  • Here, using glutathione S-transferase pulldown and caspase activity assay, we show that Smac is ineffective in relieving either caspase-7 or caspase-9 inhibition by XIAP domain fragments [23].
  • In short, HtrA2 is a Smac-like inhibitor of IAP activity with a serine protease-dependent cell death-inducing activity [24].
  • Cell cycle analysis revealed that Smac transfectants displayed significant G0/G1 arrest and reduction in 5-bromo-2'-deoxyuridine (BrdU) incorporation [25].
  • Ad CMV-Smac can combine with other proapoptotic factors, such as cisplatin, paclitaxel, and procaspase-3, to produce greater levels of apoptosis in transfected cells [4].

Physical interactions of DIABLO

  • Cleaved SMAC binds X-IAP and antagonizes its anti-apoptotic activity [26].
  • NMR studies of the antiapoptotic protein survivin have been used to determine the homodimer interface of the protein in solution and to identify residues of the protein that interact with Smac/Diablo [27].
  • Consistent with this observation was the failure of Smac protein to interact with the NAIP BIR domains [28].
  • Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition [29].
  • Here we describe second mitochondria-derived activator of caspases/Diablo as a new interacting protein of CGI-94 (comparative gene identification-94) which itself is probably involved in degenerative processes of Alzheimer's disease [30].

Regulatory relationships of DIABLO

  • These findings demonstrate that cotreatment with the N-terminus Smac/DIABLO peptide is an effective strategy to enhance apoptosis triggered by the death receptor or mitochondrial pathway and may improve the antitumor activity of Apo-2L/TRAIL and Epo B [31].
  • However, since Smac alone was sufficient to promote caspase-3 activity in vitro by inactivating XIAP, we proposed the existence of a death receptor-induced, Smac-dependent and apoptosome-independent pathway [32].
  • Prevention of the FGF-2-promoted increase in levels of functional IAPs by RNA interference or the cell-permeant Smac amino-terminal peptide blocked FGF-2-induced protection [1].
  • Through these associations, BRUCE promotes the degradation of Smac and inhibits the activity of caspase-9 but not the effector caspase, caspase-3 [33].
  • Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway [29].

Other interactions of DIABLO

  • Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain [34].
  • The presence of cIAP1 and Smac in LIGHT.LT beta R complex revealed a novel mechanism of LIGHT.LT beta R-induced apoptosis [35].
  • Our data strongly suggest that the relative ratios of XIAP (and other inhibitor-of-apoptosis proteins) to active caspase-3 and Smac may dictate, in part, whether a cell exhibits a type I or type II phenotype [32].
  • The sensitization to Apo2L/TRAIL by Smac/DIABLO overexpression was a result of synergistic activation of caspases-3, -9, and -8 [36].
  • Triple point mutants, unable to bind caspase 9, caspase 3, and DIABLO/HtrA2/Omi, were completely ineffectual in inhibiting apoptosis [37].

Analytical, diagnostic and therapeutic context of DIABLO


  1. Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. Pardo, O.E., Lesay, A., Arcaro, A., Lopes, R., Ng, B.L., Warne, P.H., McNeish, I.A., Tetley, T.D., Lemoine, N.R., Mehmet, H., Seckl, M.J., Downward, J. Mol. Cell. Biol. (2003) [Pubmed]
  2. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. Song, Z., Yao, X., Wu, M. J. Biol. Chem. (2003) [Pubmed]
  3. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Zhang, X.D., Borrow, J.M., Zhang, X.Y., Nguyen, T., Hersey, P. Oncogene (2003) [Pubmed]
  4. Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway. McNeish, I.A., Bell, S., McKay, T., Tenev, T., Marani, M., Lemoine, N.R. Exp. Cell Res. (2003) [Pubmed]
  5. Substrate cleavage by caspases generates protein fragments with Smac/Diablo-like activities. Hell, K., Saleh, M., Crescenzo, G.D., O'Connor-McCourt, M.D., Nicholson, D.W. Cell Death Differ. (2003) [Pubmed]
  6. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., Vaux, D.L. Cell (2000) [Pubmed]
  7. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Du, C., Fang, M., Li, Y., Li, L., Wang, X. Cell (2000) [Pubmed]
  8. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Fulda, S., Wick, W., Weller, M., Debatin, K.M. Nat. Med. (2002) [Pubmed]
  9. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Srinivasula, S.M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.A., Robbins, P.D., Fernandes-Alnemri, T., Shi, Y., Alnemri, E.S. Nature (2001) [Pubmed]
  10. Uncoupling of oxidative phosphorylation and Smac/DIABLO release are not sufficient to account for induction of apoptosis by sulindac sulfide in human colorectal cancer cells. Daouphars, M., Koufany, M., Benani, A., Marchal, S., Merlin, J.L., Netter, P., Jouzeau, J.Y. Int. J. Oncol. (2005) [Pubmed]
  11. Role of genomics-based strategies in overcoming chemotherapeutic resistance. Kumar, M.V., Shirley, R., Ma, Y., Lewis, R.W. Current pharmaceutical biotechnology. (2004) [Pubmed]
  12. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Chauhan, D., Li, G., Hideshima, T., Podar, K., Mitsiades, C., Mitsiades, N., Catley, L., Tai, Y.T., Hayashi, T., Shringarpure, R., Burger, R., Munshi, N., Ohtake, Y., Saxena, S., Anderson, K.C. Blood (2003) [Pubmed]
  13. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Zhang, X.D., Zhang, X.Y., Gray, C.P., Nguyen, T., Hersey, P. Cancer Res. (2001) [Pubmed]
  14. Down-regulation of FAK and IAPs by laminin during cisplatin-induced apoptosis in testicular germ cell tumors. Andjilani, M., Droz, J.P., Benahmed, M., Tabone, E. Int. J. Oncol. (2006) [Pubmed]
  15. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Deng, Y., Lin, Y., Wu, X. Genes Dev. (2002) [Pubmed]
  16. Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. Adrain, C., Creagh, E.M., Martin, S.J. EMBO J. (2001) [Pubmed]
  17. The kinetics of translocation of Smac/DIABLO from the mitochondria to the cytosol in HeLa cells. Springs, S.L., Diavolitsis, V.M., Goodhouse, J., McLendon, G.L. J. Biol. Chem. (2002) [Pubmed]
  18. The inhibitor of apoptosis protein-binding domain of Smac is not essential for its proapoptotic activity. Roberts, D.L., Merrison, W., MacFarlane, M., Cohen, G.M. J. Cell Biol. (2001) [Pubmed]
  19. Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3. You, R.I., Chen, M.C., Wang, H.W., Chou, Y.C., Lin, C.H., Hsieh, S.L. Cancer Res. (2006) [Pubmed]
  20. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Rahmani, M., Yu, C., Reese, E., Ahmed, W., Hirsch, K., Dent, P., Grant, S. Oncogene (2003) [Pubmed]
  21. Sustained release of Smac/DIABLO from mitochondria commits to undergo UVB-induced apoptosis. Takasawa, R., Tanuma, S. Apoptosis (2003) [Pubmed]
  22. Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Dai, Y., Rahmani, M., Grant, S. Oncogene (2003) [Pubmed]
  23. Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac. Huang, Y., Rich, R.L., Myszka, D.G., Wu, H. J. Biol. Chem. (2003) [Pubmed]
  24. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R. Mol. Cell (2001) [Pubmed]
  25. Role of Smac in human leukaemic cell apoptosis and proliferation. Jia, L., Patwari, Y., Kelsey, S.M., Srinivasula, S.M., Agrawal, S.G., Alnemri, E.S., Newland, A.C. Oncogene (2003) [Pubmed]
  26. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). Vucic, D., Deshayes, K., Ackerly, H., Pisabarro, M.T., Kadkhodayan, S., Fairbrother, W.J., Dixit, V.M. J. Biol. Chem. (2002) [Pubmed]
  27. Solution structure of human survivin and its binding interface with Smac/Diablo. Sun, C., Nettesheim, D., Liu, Z., Olejniczak, E.T. Biochemistry (2005) [Pubmed]
  28. Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9. Davoodi, J., Lin, L., Kelly, J., Liston, P., MacKenzie, A.E. J. Biol. Chem. (2004) [Pubmed]
  29. Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway. Ma, L., Huang, Y., Song, Z., Feng, S., Tian, X., Du, W., Qiu, X., Heese, K., Wu, M. Cell Death Differ. (2006) [Pubmed]
  30. Comparative gene identification-94--a pivotal regulator of apoptosis. Heese, K., Nagai, Y., Sawada, T. Neuroscience (2003) [Pubmed]
  31. Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Guo, F., Nimmanapalli, R., Paranawithana, S., Wittman, S., Griffin, D., Bali, P., O'Bryan, E., Fumero, C., Wang, H.G., Bhalla, K. Blood (2002) [Pubmed]
  32. Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mitochondrial release of Smac/DIABLO and subsequent inactivation of X-linked inhibitor-of-apoptosis protein. Sun, X.M., Bratton, S.B., Butterworth, M., MacFarlane, M., Cohen, G.M. J. Biol. Chem. (2002) [Pubmed]
  33. The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. Qiu, X.B., Goldberg, A.L. J. Biol. Chem. (2005) [Pubmed]
  34. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Liu, Z., Sun, C., Olejniczak, E.T., Meadows, R.P., Betz, S.F., Oost, T., Herrmann, J., Wu, J.C., Fesik, S.W. Nature (2000) [Pubmed]
  35. Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. Kuai, J., Nickbarg, E., Wooters, J., Qiu, Y., Wang, J., Lin, L.L. J. Biol. Chem. (2003) [Pubmed]
  36. X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/DIABLO). Ng, C.P., Bonavida, B. Mol. Cancer Ther. (2002) [Pubmed]
  37. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. Silke, J., Hawkins, C.J., Ekert, P.G., Chew, J., Day, C.L., Pakusch, M., Verhagen, A.M., Vaux, D.L. J. Cell Biol. (2002) [Pubmed]
  38. Cisplatin-induced apoptosis in Hep3B cells: mitochondria-dependent and -independent pathways. Kim, J.S., Lee, J.M., Chwae, Y.J., Kim, Y.H., Lee, J.H., Kim, K., Lee, T.H., Kim, S.J., Park, J.H. Biochem. Pharmacol. (2004) [Pubmed]
  39. The inhibitor of apoptosis protein family and its antagonists in acute leukemias. Wrzesień-Kuś, A., Smolewski, P., Sobczak-Pluta, A., Wierzbowska, A., Robak, T. Apoptosis (2004) [Pubmed]
  40. Antiapoptotic function of apoptosis inhibitor 2-MALT1 fusion protein involved in t(11;18)(q21;q21) mucosa-associated lymphoid tissue lymphoma. Hosokawa, Y., Suzuki, H., Suzuki, Y., Takahashi, R., Seto, M. Cancer Res. (2004) [Pubmed]
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