DIABLO (diablo, IAP-binding mitochondrial protein)

2013-02-01 Gisela Ceballos-Cancino , Jorge Melendez-Zajgla Affiliation

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

Identity

HGNC

DIABLO

LOCATION

12q24.31

LOCUSID

56616

ALIAS

DFNA64,SMAC

FUSION GENES

Show Gene Fusions

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).

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).

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

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 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

Gene ID	Transcript ID	Uniprot
ENSG00000184047	ENST00000267169	A0A2U3TZH2
ENSG00000184047	ENST00000342392	F5GXT8
ENSG00000184047	ENST00000353548	Q9NR28
ENSG00000184047	ENST00000353548	A0A0S2Z5P6
ENSG00000184047	ENST00000439489	H7BZQ7
ENSG00000184047	ENST00000446652	H7BZK7
ENSG00000184047	ENST00000464942	Q9NR28
ENSG00000184047	ENST00000464942	A0A0S2Z5U7
ENSG00000184047	ENST00000540535	F5GX50
ENSG00000184047	ENST00000541273	F5GXT8
ENSG00000184047	ENST00000541656	F5GYH3
ENSG00000184047	ENST00000644227	A0A2R8Y5H2
ENSG00000184047	ENST00000650715	Q9NR28
ENSG00000184047	ENST00000650715	A0A0S2Z5U7

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Apoptosis	KEGG	ko04210
Apoptosis	KEGG	hsa04210
Programmed Cell Death	REACTOME	R-HSA-5357801
Apoptosis	REACTOME	R-HSA-109581
Intrinsic Pathway for Apoptosis	REACTOME	R-HSA-109606
Release of apoptotic factors from the mitochondria	REACTOME	R-HSA-111457
Apoptotic factor-mediated response	REACTOME	R-HSA-111471
SMAC-mediated apoptotic response	REACTOME	R-HSA-111469
SMAC binds to IAPs	REACTOME	R-HSA-111463
SMAC-mediated dissociation of IAP:caspase complexes	REACTOME	R-HSA-111464
Apoptosis - multiple species	KEGG	ko04215
Apoptosis - multiple species	KEGG	hsa04215

Protein levels (Protein atlas)

Not detected

Low

Medium

High

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/teaching-explorer/case-report-explorer/css/lib/bootstrap.min.css