DIABLO (diablo, IAP-binding mitochondrial protein)

2013-02-01   Gisela 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




Atlas Image
Structure of Smac gene and its transcripts.


The gene encompasses 19.86 kb of DNA; 7 exons.


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).


Atlas Image
Structure of Smac. Smac is a protein of 239 aa. MTS: mitochondrial targeting sequence; IBM: IAP-binding motif; aa: aminoacids.


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).


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).


Mitochondrial (Du et al., 2000), cytosolic, after apoptosis activation (Du et al., 2000; Verhagen et al., 2000).


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).


The gene in conserved in chimpanzee, dog, cow, mouse, rat, chicken and zebrafish.



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

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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).
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Hepatocellular carcinoma
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).
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Pancreatic cancer
Smac protein, by immunohistochemistry analysis, was significantly upregulated in pancreatic tumours. Smac expression was correlated only with pathological grade (p
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Bladder cancer
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).
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Breast cancer
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).
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Endometrioid endometrial cancer
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).
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Ovarian mucinous tumor
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).
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Lung cancer
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).
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Non-small cell lung cancer
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).
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Prostate cancer
Smac protein is increased in prostate cancer and correlates with high Gleason score (sum=8-10) (Grubb et al., 2009).
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Colorectal cancer
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 Dukes staging and lymph node metastases (Endo et al., 2009).
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Testicular germ cell tumours
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).
The 12q24.31 region is frequently deleted in early stages of MF (Carbone et al., 2008).
The most frequent form of cutaneous T cell lymphoma.
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Renal cell carcinoma
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).
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Cervical cancer
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).
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B-cell non-Hodgkin and Hodgkin lymphomas
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).
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Acute leukemia (AL)
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).
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Chronic lymphocytic leukemia (CLL)
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, theres 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).


Pubmed IDLast YearTitleAuthors
170673902006High Smac/DIABLO expression is associated with early local recurrence of cervical cancer.Arellano-Llamas A et al
205379842010Hip2 interacts with and destabilizes Smac/DIABLO.Bae Y et al
170853462006Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma.Bao ST et al
186637542008Array-based comparative genomic hybridization in early-stage mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF.Carbone A et al
202108902010Prognostic 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 et al
217228592011Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64.Cheng J et al
214781152010Prognostic significance of smac/DIABLO in endometrioid endometrial cancer.Dobrzycka B et al
109297112000Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.Du C et al
191485072009Clinical significance of Smac/DIABLO expression in colorectal cancer.Endo K et al
155608492004SMAC is expressed de novo in a subset of cervical cancer tumors.Espinosa M et al
192752042009Pathway biomarker profiling of localized and metastatic human prostate cancer reveal metastatic and prognostic signatures.Grubb RL et al
200453092010Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia.Grzybowska-Izydorczyk O et al
153002552004Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function.Hao Y et al
190883732008Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by preeclampsia.Heazell AE et al
225345372012Clinical significance of Smac and Ki-67 expression in pancreatic cancer.Hu HY et al
125255022003Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO.Hu S et al
189793982008[Expression levels of the IAP antagonists XAF1, Smac/DIABLO and HtrA2 in testicular germ cell tumours].Kempkensteffen C et al
170459682006Nuclear interaction of Smac/DIABLO with Survivin at G2/M arrest prompts docetaxel-induced apoptosis in DU145 prostate cancer cells.Kim JY et al
162311802006Expression of apoptosome pathway-related transcripts in non-small cell lung cancer.Krepela E et al
167290332006Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway.Ma L et al
121219692002Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro.MacFarlane M et al
221611562012Reciprocal expression of survivin and SMAC/DIABLO in primary breast cancer.Mansour A et al
173203502007Apoptosis induced by cAMP requires Smac/DIABLO transcriptional upregulation.Martinez-Velazquez M et al
222185302012Low circulating serum levels of second mitochondria-derived activator of caspase (Smac/DIABLO) in patients with bladder cancer.Mizutani Y et al
157498262005X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO.Morizane Y et al
176864592007Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP.Park BD et al
217449972011Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients.Pluta P et al
227511252013An apoptosis-independent role of SMAC in tumor suppression.Qiu W et al
155074512005The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9.Qiu XB et al
169496412006Expression of Smac/DIABLO in B-cell non-Hodgkin and Hodgkin lymphomas.Ren Y et al
151838962004Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia.Schliep S et al
150108752004Expression of Smac/DIABLO is a novel prognostic marker in lung cancer.Sekimura A et al
126602402003Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis.Song Z et al
109509472000Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway.Srinivasula SM et al
109297122000Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.Verhagen AM et al
118016032002SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP).Vucic D et al
210551552010[Expression and significance of Survivin and Smac in ovarian mucinous tumors].Wang HX et al
166381832006[Expressions of c-IAP2 and Smac gene in leukemia and their clinical significance].Wang Y et al
159022962005Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL).Winkler D et al
166171452006Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1.Xie W et al
216454092011X-linked inhibitor of apoptosis positive nuclear labeling: a new independent prognostic biomarker of breast invasive ductal carcinoma.Zhang Y et al

Other Information

Locus ID:

NCBI: 56616
MIM: 605219
HGNC: 21528
Ensembl: ENSG00000184047


dbSNP: 56616
ClinVar: 56616
TCGA: ENSG00000184047


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Programmed Cell DeathREACTOMER-HSA-5357801
Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
Release of apoptotic factors from the mitochondriaREACTOMER-HSA-111457
Apoptotic factor-mediated responseREACTOMER-HSA-111471
SMAC-mediated apoptotic responseREACTOMER-HSA-111469
SMAC binds to IAPsREACTOMER-HSA-111463
SMAC-mediated dissociation of IAP:caspase complexesREACTOMER-HSA-111464
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
179966482007Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis.249
121182452002Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo.147
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
153002552004Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function.73
121219692002Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro.71
125255022003Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO.70
162823252006Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases.61
149605762004Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells.58
265673622015Promises and Challenges of Smac Mimetics as Cancer Therapeutics.57
129753472003Real-time single cell analysis of Smac/DIABLO release during apoptosis.51


Gisela Ceballos-Cancino ; Jorge Melendez-Zajgla

DIABLO (diablo, IAP-binding mitochondrial protein)

Atlas Genet Cytogenet Oncol Haematol. 2013-02-01

Online version: http://atlasgeneticsoncology.org/gene/42995/diablo-(diablo-iap-binding-mitochondrial-protein)