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DIABLO (diablo, IAP-binding mitochondrial protein)

Written2013-02Gisela Ceballos-Cancino, Jorge Melendez-Zajgla
Cancer Functional Genomics Laboratory, National Institute of Genomic Medicine, Periferico Sur 4124, Sexto Piso, Torre Zafiro II, Col Ex Rancho de Anzaldo, Alvaro Obregon, 01900 Mexico City, Mexico

(Note : for Links provided by Atlas : click)

Identity

Other aliasDFNA64
DIABLO-S
SMAC
SMAC3
LocusID (NCBI) 56616
Atlas_Id 42995
Location 12q24.31  [Link to chromosome band 12q24]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
AARSD1 (17q21.31) / DIABLO (12q24.31)DIABLO (12q24.31) / LRRC47 (1p36.32)

DNA/RNA

 
  Structure of Smac gene and its transcripts.
Description The gene encompasses 19.86 kb of DNA; 7 exons.
Transcription mRNA 2265 pb; ORF 720 pb.
Smac promoter contains a functional CRE site which is regulated by cAMP for apoptosis modulation (Martinez-Velazquez et al., 2007). Another transcriptional regulator for Smac is E2F1 which have two binding sites in the Smac promoter. Positive regulation of Smac by E2F1 results in enhanced mitochondria-mediated apoptosis (Xie et al., 2006).

Protein

 
  Structure of Smac. Smac is a protein of 239 aa. MTS: mitochondrial targeting sequence; IBM: IAP-binding motif; aa: aminoacids.
Description Precursor 239 aa (27.131 kDa), mature 184 aa (20.765 kDa).
- aa 1-55, mitonchondrial targeting sequence (MTS)
- aa 56-60 (AVPI) IAP-binding motif (IBM).
Post translational modifications:
- Ubiquitination, Hip2 (Bae, 2010), Livin (Ma, 2006), XIAP (Morizane, 2005; MacFarlane, 2002), cIAP1 (Hu and Yang, 2003), cIAP2 (Hu and Yang, 2003), Apollon (Hao et al., 2004).
- Phosphorylation, JNK3 (Park et al., 2007).
Expression Ubiquitously, highest in adult testis and high in heart, liver, kidney, spleen, prostate and ovary. Smac mRNA is low in brain, lung, thymus and peripheral blood leukocytes (Du et al., 2000).
Localisation Mitochondrial (Du et al., 2000), cytosolic, after apoptosis activation (Du et al., 2000; Verhagen et al., 2000).
Function Proapoptotic protein. Smac participates in both apoptotic pathways, intrinsic and extrinsic. Mature Smac localizes in mitochondria and after an apoptotic stimulus is released into the cytosol where it bind IAPs and neutralizes its inhibitory action on caspases (Du et al., 2000; Verhagen et al., 2000). From the IAP family, Smac interacts with and inhibit XIAP (Du et al., 2000; Srinivasula et al., 2000), cIAP1 (Hu and Yang, 2003), cIAP2 (Hu and Yang, 2003), Survivin (Song et al., 2003; Kim et al., 2006), Apollon (Hao et al., 2004; Qiu and Goldberg, 2005) and ML-IAP/BIRC7 (Vucic, 2002). Recently, an apoptosis-independent role for Smac in colon cancer has been described. Loss of Smac induces cIAP1 and cIAP2 upregulation, increased proliferation and activation of the NF-kB p65 subunit (Qiu et al., 2012).
Homology The gene in conserved in chimpanzee, dog, cow, mouse, rat, chicken and zebrafish.

Mutations

Germinal A heterozygous missense mutation, c.377C>T, in Smac, is genetically linked to progressive, non-syndromic, sensorineural hearing loss in an extended Chinese DFNA64 family. Prediction by molecular modeling localizes this mutation at the end of the arch-shaped H1 helix, far away from the binding site to IAPs. Although the mutation does not alters the apoptotic function of Smac, ectopic expression of the mutant induces degradation of both, endogenous and mutant Smac through heterodimerization between them (Cheng et al., 2011).

Implicated in

Note
  
Entity Preeclampsia
Note Significantly elevated levels of Smac were found in villous trophoblast in pregnancies complicated by preeclampsia in comparison with normal pregnancies. This upregulation may be related to increased apoptosis in preeclampsia (Heazell et al., 2008).
  
  
Entity Hepatocellular carcinoma
Note mRNA and protein expression of Smac was significantly different in tissues of hepatocellular carcinoma and non hepatocellular carcinoma tissues. Smac expression is diminished in carcinoma (Bao et al., 2006).
  
  
Entity Pancreatic cancer
Note Smac protein, by immunohistochemistry analysis, was significantly upregulated in pancreatic tumours. Smac expression was correlated only with pathological grade (p<0.05) (Hu et al., 2012).
  
  
Entity Bladder cancer
Note Smac expression is downregulated in bladder cancer, this reduced level predicts a worse prognosis (Mizutani et al., 2010). Even, the mean serum level of Smac was reduced 2-fold in bladder cancer patients in comparison with normal donors. The mean serum level of Smac either was reduced in patients with an advanced stage and grade tumor. Lower serum level of smac predicted early recurrence in patients with bladder cancer (Mizutani et al., 2012).
  
  
Entity Breast cancer
Note Smac expression is reduced in breast cancer and inversely correlates with the tumor stage (Pluta et al., 2011). Smac expression is more prevalent in the HER2 positive group than negative group (Zhang et al., 2011). Additonally, Smac mRNA expression is downregulated in breast cancer samples and shows an inverse correlation with survivin mRNA expression (Mansour et al., 2012).
  
  
Entity Endometrioid endometrial cancer
Note Smac protein expression correlates with tumor grade. Negative expression of Smac is a sign of poor prognostic in this kind of tumor (Dobrzycka et al., 2010).
  
  
Entity Ovarian mucinous tumor
Note Smac protein expression is downregulated in this tumor. Smac expression inversely correlates with Survivin expression. Analysis of subcellular localization of Smac demonstrate that Smac protein exist mainly in the intermembranal space of the mitochondria (Wang et al., 2010).
  
  
Entity Lung cancer
Note Smac mRNA expression is lower in primary lung cancer than in normal tissues. In squamous cell carcinomas the expression of Smac is more reduced than in adenocarcinomas. In tumours of smokers the expression of Smac mRNA is lower than in tumours of non smokers. Smac expression correlates inversely with stage tumour and low expression is sign of worse prognostic (Sekimura et al., 2004).
  
  
Entity Non-small cell lung cancer
Note Smac mRNA expression is significantly increased in NSCLC tissues in comparison with lung tissue (Krepela et al., 2006). In advanced NSCLC high smac mRNA expression correlates with longer progression-free survival (PFS) and overall survival (OS). Smac is an independent prognostic factor for OS, but not for FPS (Chen et al., 2010).
  
  
Entity Prostate cancer
Note Smac protein is increased in prostate cancer and correlates with high Gleason score (sum=8-10) (Grubb et al., 2009).
  
  
Entity Colorectal cancer
Note Patients with smac-negative cancer have higher incidence of lymph node and distant metastases than smac positive-cancer. Negative expression of Smac predicts poorer survival and is a prognostic indicator independent of Duke's staging and lymph node metastases (Endo et al., 2009).
  
  
Entity Testicular germ cell tumours
Note Smac mRNA is downregulated during the development and progression of TGCT. While Smac mRNA is downregulated XIAP mRNA expression is unchanged, and patients with high ratio XIAP:Smac are likely in clinical stage III (Kempkensteffen et al., 2007; Kempkensteffen et al., 2008b).
  
  
Entity Mycosis fungoides
Note The 12q24.31 region is frequently deleted in early stages of MF (Carbone et al., 2008).
Disease The most frequent form of cutaneous T cell lymphoma.
  
  
Entity Renal cell carcinoma
Note Smac protein expression is downregulated in RCC and no expression of Smac predicts a worse prognosis (Mizutani et al., 2005). Either Smac mRNA expression is inversely associated with outcome of RCC patients (Kempkensteffen et al., 2008a).
  
  
Entity Cervical cancer
Note Smac mRNA is expressed de novo in cervical cancer, although no correlation with any clinical variable was found (Espinosa et al., 2004). However, Smac protein expression correlates with microvascular density, a marker for angiogenesis (Arellano-Llamas et al., 2006).
  
  
Entity B-cell non-Hodgkin and Hodgkin lymphomas
Note Smac protein is expressed in almost fifty percent of NHL and HL tissues. Smac protein is differentially expressed in various NHL types while all HL types were positive for Smac (Ren et al., 2006).
  
  
Entity Acute leukemia (AL)
Note Smac mRNA expression is increased in de novo AL patients in comparison with normal controls and the levels decrease in patients at complete remission. In relapsed patients the levels of Smac are increased again. Smac expression in AL is related to remission rate, patients with high levels of Smac have low remission rates. Smac expression could serve like a marker of prognosis in AL (Wang and Zhou, 2006).
  
  
Entity Chronic lymphocytic leukemia (CLL)
Note An increased expression of Smac has been observed in CLL samples. Possibly, these high levels of Smac in CLL could prevent the inhibitory effect of XIAP on caspases, since in conditions where XIAP is upregulated and apoptosis is prevented, there's no caspase inhibition (Schliep et al., 2004; Winkler et al., 2005). However, downregulation of Smac has been also observed in CLL samples. Higher expression of IAPs and lower levels of Smac were found in patients with progressive disease, compared with those with stable CLL (Ren et al., 2006; Grzybowska-Izydorczyk et al., 2010).
  

Bibliography

High Smac/DIABLO expression is associated with early local recurrence of cervical cancer.
Arellano-Llamas A, Garcia FJ, Perez D, Cantu D, Espinosa M, De la Garza JG, Maldonado V, Melendez-Zajgla J.
BMC Cancer. 2006 Oct 26;6:256.
PMID 17067390
 
Hip2 interacts with and destabilizes Smac/DIABLO.
Bae Y, Kho CW, Lee SY, Rhim H, Kang S.
Biochem Biophys Res Commun. 2010 Jul 9;397(4):718-23. doi: 10.1016/j.bbrc.2010.06.016. Epub 2010 Jun 9.
PMID 20537984
 
Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma.
Bao ST, Gui SQ, Lin MS.
Hepatobiliary Pancreat Dis Int. 2006 Nov;5(4):580-3.
PMID 17085346
 
Array-based comparative genomic hybridization in early-stage mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF.
Carbone A, Bernardini L, Valenzano F, Bottillo I, De Simone C, Capizzi R, Capalbo A, Romano F, Novelli A, Dallapiccola B, Amerio P.
Genes Chromosomes Cancer. 2008 Dec;47(12):1067-75. doi: 10.1002/gcc.20601.
PMID 18663754
 
Prognostic value of survivin, X-linked inhibitor of apoptosis protein and second mitochondria-derived activator of caspases expression in advanced non-small-cell lung cancer patients.
Chen P, Li J, Ge LP, Dai CH, Li XQ.
Respirology. 2010 Apr;15(3):501-9. doi: 10.1111/j.1440-1843.2010.01710.x. Epub 2010 Feb 24.
PMID 20210890
 
Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64.
Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, Petrillo M, Wrzeszczynski KO, Yang S, Dai P, Zhai S, Han D, Zhang MQ, Li W, Liu X, Li H, Chen ZY, Yuan H.
Am J Hum Genet. 2011 Jul 15;89(1):56-66. doi: 10.1016/j.ajhg.2011.05.027. Epub 2011 Jun 30.
PMID 21722859
 
Prognostic significance of smac/DIABLO in endometrioid endometrial cancer.
Dobrzycka B, Terlikowski SJ, Bernaczyk PS, Garbowicz M, Niklinski J, Chyczewski L, Kulikowski M.
Folia Histochem Cytobiol. 2010 Dec;48(4):678-81. doi: 10.2478/v10042-010-0091-2.
PMID 21478115
 
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 Jul 7;102(1):33-42.
PMID 10929711
 
Clinical significance of Smac/DIABLO expression in colorectal cancer.
Endo K, Kohnoe S, Watanabe A, Tashiro H, Sakata H, Morita M, Kakeji Y, Maehara Y.
Oncol Rep. 2009 Feb;21(2):351-5.
PMID 19148507
 
SMAC is expressed de novo in a subset of cervical cancer tumors.
Espinosa M, Cantu D, Lopez CM, De la Garza JG, Maldonado VA, Melendez-Zajgla J.
BMC Cancer. 2004 Nov 23;4:84.
PMID 15560849
 
Pathway biomarker profiling of localized and metastatic human prostate cancer reveal metastatic and prognostic signatures.
Grubb RL, Deng J, Pinto PA, Mohler JL, Chinnaiyan A, Rubin M, Linehan WM, Liotta LA, Petricoin EF, Wulfkuhle JD.
J Proteome Res. 2009 Jun;8(6):3044-54. doi: 10.1021/pr8009337.
PMID 19275204
 
Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia.
Grzybowska-Izydorczyk O, Cebula B, Robak T, Smolewski P.
Eur J Cancer. 2010 Mar;46(4):800-10. doi: 10.1016/j.ejca.2009.11.023. Epub 2010 Jan 4.
PMID 20045309
 
Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function.
Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H, Katayama R, Hashimoto C, Zhang X, Noda T, Tsuruo T, Naito M.
Nat Cell Biol. 2004 Sep;6(9):849-60. Epub 2004 Aug 8.
PMID 15300255
 
Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by preeclampsia.
Heazell AE, Buttle HR, Baker PN, Crocker IP.
Reprod Sci. 2008 Dec;15(10):1034-43. doi: 10.1177/1933719108322438.
PMID 19088373
 
Clinical significance of Smac and Ki-67 expression in pancreatic cancer.
Hu HY, Liu H, Zhang JW, Hu K, Lin Y.
Hepatogastroenterology. 2012 Nov-Dec;59(120):2640-3.
PMID 22534537
 
Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO.
Hu S, Yang X.
J Biol Chem. 2003 Mar 21;278(12):10055-60. Epub 2003 Jan 13.
PMID 12525502
 
[Expression levels of the IAP antagonists XAF1, Smac/DIABLO and HtrA2 in testicular germ cell tumours].
Kempkensteffen C, Hinz S, Jager T, Weikert S, Krause H, Schostak M, Christoph F, Strenziok R, Miller K, Schrader M.
Aktuelle Urol. 2008b Nov;39(6):436-41. doi: 10.1055/s-2008-1038283. Epub 2008 Oct 31.
PMID 18979398
 
Nuclear interaction of Smac/DIABLO with Survivin at G2/M arrest prompts docetaxel-induced apoptosis in DU145 prostate cancer cells.
Kim JY, Chung JY, Lee SG, Kim YJ, Park JE, Yoo KS, Yoo YH, Park YC, Kim BG, Kim JM.
Biochem Biophys Res Commun. 2006 Dec 1;350(4):949-54. Epub 2006 Oct 5.
PMID 17045968
 
Expression of apoptosome pathway-related transcripts in non-small cell lung cancer.
Krepela E, Prochazka J, Fiala P, Zatloukal P, Selinger P.
J Cancer Res Clin Oncol. 2006 Jan;132(1):57-68. Epub 2005 Oct 18.
PMID 16231180
 
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 Dec;13(12):2079-88. Epub 2006 May 26.
PMID 16729033
 
Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro.
MacFarlane M, Merrison W, Bratton SB, Cohen GM.
J Biol Chem. 2002 Sep 27;277(39):36611-6. Epub 2002 Jul 16.
PMID 12121969
 
Reciprocal expression of survivin and SMAC/DIABLO in primary breast cancer.
Mansour A, Nabil M, Ali-Labib R, Said H, Annos F.
Med Oncol. 2012 Dec;29(4):2535-42. doi: 10.1007/s12032-011-0129-0. Epub 2011 Dec 8.
PMID 22161156
 
Apoptosis induced by cAMP requires Smac/DIABLO transcriptional upregulation.
Martinez-Velazquez M, Melendez-Zajgla J, Maldonado V.
Cell Signal. 2007 Jun;19(6):1212-20. Epub 2007 Jan 21.
PMID 17320350
 
Low circulating serum levels of second mitochondria-derived activator of caspase (Smac/DIABLO) in patients with bladder cancer.
Mizutani Y, Katsuoka Y, Bonavida B.
Int J Oncol. 2012 Apr;40(4):1246-50. doi: 10.3892/ijo.2012.1324. Epub 2012 Jan 3.
PMID 22218530
 
X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO.
Morizane Y, Honda R, Fukami K, Yasuda H.
J Biochem. 2005 Feb;137(2):125-32.
PMID 15749826
 
Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP.
Park BD, Ham YM, Jeong HJ, Cho SJ, Je YT, Yoo KD, Lee SK.
Biochem Biophys Res Commun. 2007 Oct 5;361(4):994-9. Epub 2007 Jul 31.
PMID 17686459
 
Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients.
Pluta P, Cebula-Obrzut B, Ehemann V, Pluta A, Wierzbowska A, Piekarski J, Bilski A, Nejc D, Kordek R, Robak T, Smolewski P, Jeziorski A.
Neoplasma. 2011;58(5):430-5.
PMID 21744997
 
An apoptosis-independent role of SMAC in tumor suppression.
Qiu W, Liu H, Sebastini A, Sun Q, Wang H, Zhang L, Yu J.
Oncogene. 2012 Jul 2. doi: 10.1038/onc.2012.265. [Epub ahead of print]
PMID 22751125
 
The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9.
Qiu XB, Goldberg AL.
J Biol Chem. 2005 Jan 7;280(1):174-82. Epub 2004 Oct 26.
PMID 15507451
 
Expression of Smac/DIABLO in B-cell non-Hodgkin and Hodgkin lymphomas.
Ren Y, Akyurek N, Schlette E, Rassidakis GZ, Medeiros LJ.
Hum Pathol. 2006 Nov;37(11):1407-13. Epub 2006 Sep 1.
PMID 16949641
 
Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia.
Schliep S, Decker T, Schneller F, Wagner H, Hacker G.
Exp Hematol. 2004 Jun;32(6):556-62.
PMID 15183896
 
Expression of Smac/DIABLO is a novel prognostic marker in lung cancer.
Sekimura A, Konishi A, Mizuno K, Kobayashi Y, Sasaki H, Yano M, Fukai I, Fujii Y.
Oncol Rep. 2004 Apr;11(4):797-802.
PMID 15010875
 
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 Jun 20;278(25):23130-40. Epub 2003 Mar 26.
PMID 12660240
 
Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway.
Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang Z, Alnemri ES.
J Biol Chem. 2000 Nov 17;275(46):36152-7.
PMID 10950947
 
Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL.
Cell. 2000 Jul 7;102(1):43-53.
PMID 10929712
 
SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP).
Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ, Dixit VM.
J Biol Chem. 2002 Apr 5;277(14):12275-9. Epub 2002 Jan 18.
PMID 11801603
 
[Expression and significance of Survivin and Smac in ovarian mucinous tumors].
Wang HX, Chen G, Li GL, Jiang YJ.
Zhonghua Bing Li Xue Za Zhi. 2010 Jun;39(6):387-90.
PMID 21055155
 
[Expressions of c-IAP2 and Smac gene in leukemia and their clinical significance].
Wang Y, Zhou JH.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006 Apr;14(2):217-20.
PMID 16638183
 
Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL).
Winkler D, Schneider C, Krober A, Pasqualucci L, Lichter P, Dohner H, Stilgenbauer S.
Leukemia. 2005 Jul;19(7):1211-5.
PMID 15902296
 
Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1.
Xie W, Jiang P, Miao L, Zhao Y, Zhimin Z, Qing L, Zhu WG, Wu M.
Nucleic Acids Res. 2006 Apr 14;34(7):2046-55. Print 2006.
PMID 16617145
 
X-linked inhibitor of apoptosis positive nuclear labeling: a new independent prognostic biomarker of breast invasive ductal carcinoma.
Zhang Y, Zhu J, Tang Y, Li F, Zhou H, Peng B, Zhou C, Fu R.
Diagn Pathol. 2011 Jun 7;6:49. doi: 10.1186/1746-1596-6-49.
PMID 21645409
 

Citation

This paper should be referenced as such :
Ceballos-Cancino, G ; Melendez-Zajgla, J
DIABLO (diablo, IAP-binding mitochondrial protein)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(7):478-482.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/DIABLOID42995ch12q24.html


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Nomenclature
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AtlasDIABLOID42995ch12q24.txt
Aliases
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Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)56616
Protein : pattern, domain, 3D structure
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