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

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