DIABLO (diablo, IAP-binding mitochondrial protein)
2013-02-01 Gisela Ceballos-Cancino , Jorge Melendez-Zajgla AffiliationCancer 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
Identity
HGNC
LOCATION
12q24.31
LOCUSID
ALIAS
DFNA64,SMAC
FUSION GENES
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).
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).
Proteins
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).
- 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
Entity name
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 name
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 name
Pancreatic cancer
Note
Smac protein, by immunohistochemistry analysis, was significantly upregulated in pancreatic tumours. Smac expression was correlated only with pathological grade (p
Entity name
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 name
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 name
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 name
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 name
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 name
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 name
Prostate cancer
Note
Smac protein is increased in prostate cancer and correlates with high Gleason score (sum=8-10) (Grubb et al., 2009).
Entity name
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 Dukes staging and lymph node metastases (Endo et al., 2009).
Entity name
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 name
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 name
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 name
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 name
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 name
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 name
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, 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).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17067390 | 2006 | High Smac/DIABLO expression is associated with early local recurrence of cervical cancer. | Arellano-Llamas A et al |
| 20537984 | 2010 | Hip2 interacts with and destabilizes Smac/DIABLO. | Bae Y et al |
| 17085346 | 2006 | Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma. | Bao ST et al |
| 18663754 | 2008 | Array-based comparative genomic hybridization in early-stage mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF. | Carbone A et al |
| 20210890 | 2010 | 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 et al |
| 21722859 | 2011 | Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. | Cheng J et al |
| 21478115 | 2010 | Prognostic significance of smac/DIABLO in endometrioid endometrial cancer. | Dobrzycka B et al |
| 10929711 | 2000 | Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. | Du C et al |
| 19148507 | 2009 | Clinical significance of Smac/DIABLO expression in colorectal cancer. | Endo K et al |
| 15560849 | 2004 | SMAC is expressed de novo in a subset of cervical cancer tumors. | Espinosa M et al |
| 19275204 | 2009 | Pathway biomarker profiling of localized and metastatic human prostate cancer reveal metastatic and prognostic signatures. | Grubb RL et al |
| 20045309 | 2010 | Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia. | Grzybowska-Izydorczyk O et al |
| 15300255 | 2004 | Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. | Hao Y et al |
| 19088373 | 2008 | Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by preeclampsia. | Heazell AE et al |
| 22534537 | 2012 | Clinical significance of Smac and Ki-67 expression in pancreatic cancer. | Hu HY et al |
| 12525502 | 2003 | Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. | Hu S et al |
| 18979398 | 2008 | [Expression levels of the IAP antagonists XAF1, Smac/DIABLO and HtrA2 in testicular germ cell tumours]. | Kempkensteffen C et al |
| 17045968 | 2006 | Nuclear interaction of Smac/DIABLO with Survivin at G2/M arrest prompts docetaxel-induced apoptosis in DU145 prostate cancer cells. | Kim JY et al |
| 16231180 | 2006 | Expression of apoptosome pathway-related transcripts in non-small cell lung cancer. | Krepela E et al |
| 16729033 | 2006 | Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway. | Ma L et al |
| 12121969 | 2002 | Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. | MacFarlane M et al |
| 22161156 | 2012 | Reciprocal expression of survivin and SMAC/DIABLO in primary breast cancer. | Mansour A et al |
| 17320350 | 2007 | Apoptosis induced by cAMP requires Smac/DIABLO transcriptional upregulation. | Martinez-Velazquez M et al |
| 22218530 | 2012 | Low circulating serum levels of second mitochondria-derived activator of caspase (Smac/DIABLO) in patients with bladder cancer. | Mizutani Y et al |
| 15749826 | 2005 | X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO. | Morizane Y et al |
| 17686459 | 2007 | Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP. | Park BD et al |
| 21744997 | 2011 | Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients. | Pluta P et al |
| 22751125 | 2013 | An apoptosis-independent role of SMAC in tumor suppression. | Qiu W et al |
| 15507451 | 2005 | The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. | Qiu XB et al |
| 16949641 | 2006 | Expression of Smac/DIABLO in B-cell non-Hodgkin and Hodgkin lymphomas. | Ren Y et al |
| 15183896 | 2004 | Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia. | Schliep S et al |
| 15010875 | 2004 | Expression of Smac/DIABLO is a novel prognostic marker in lung cancer. | Sekimura A et al |
| 12660240 | 2003 | Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. | Song Z et al |
| 10950947 | 2000 | Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. | Srinivasula SM et al |
| 10929712 | 2000 | Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. | Verhagen AM et al |
| 11801603 | 2002 | SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). | Vucic D et al |
| 21055155 | 2010 | [Expression and significance of Survivin and Smac in ovarian mucinous tumors]. | Wang HX et al |
| 16638183 | 2006 | [Expressions of c-IAP2 and Smac gene in leukemia and their clinical significance]. | Wang Y et al |
| 15902296 | 2005 | Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL). | Winkler D et al |
| 16617145 | 2006 | Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1. | Xie W et al |
| 21645409 | 2011 | X-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
Variants:
dbSNP: 56616
ClinVar: 56616
TCGA: ENSG00000184047
COSMIC: DIABLO
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36758104 | 2023 | Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. | 6 |
| 36758105 | 2023 | Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. | 8 |
| 37522329 | 2023 | AREL1 resists the apoptosis induced by TGF-β by inhibiting SMAC in vascular endothelial cells. | 1 |
| 36758104 | 2023 | Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. | 6 |
| 36758105 | 2023 | Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. | 8 |
| 37522329 | 2023 | AREL1 resists the apoptosis induced by TGF-β by inhibiting SMAC in vascular endothelial cells. | 1 |
| 35006369 | 2022 | Co-overexpression of TRAIL and Smac sensitizes MDA-MB-231 cells to radiation through apoptosis depending on mitochondrial pathway. | 1 |
| 35281523 | 2022 | LINC-DUBR Suppresses Malignant Progression of Ovarian Cancer by Downregulating miR-107 to Induce SMAC Expression. | 7 |
| 35006369 | 2022 | Co-overexpression of TRAIL and Smac sensitizes MDA-MB-231 cells to radiation through apoptosis depending on mitochondrial pathway. | 1 |
| 35281523 | 2022 | LINC-DUBR Suppresses Malignant Progression of Ovarian Cancer by Downregulating miR-107 to Induce SMAC Expression. | 7 |
| 33179373 | 2021 | Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer. | 12 |
| 33558564 | 2021 | BAX and SMAC regulate bistable properties of the apoptotic caspase system. | 9 |
| 33770100 | 2021 | Induction of interferon-β and interferon signaling by TRAIL and Smac mimetics via caspase-8 in breast cancer cells. | 4 |
| 34247143 | 2021 | Biophysical characterization of the interaction between the full-length XIAP and Smac/DIABLO. | 2 |
| 33179373 | 2021 | Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer. | 12 |
Citation
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
