AVEN (apoptosis, caspase activation inhibitor)

Written2013-10Inga Maria Melzer, Martin Zörnig
Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany

(Note : for Links provided by Atlas : click)

1. Identity

Alias_symbol (synonym)
General Information
Other alias
LocusID (NCBI) 57099
Atlas_Id 43158
Location 15q14  [Link to chromosome band 15q14]
Location_base_pair Starts at 33866227 and ends at 34039102 bp from pter ( according to hg19-Feb_2009)  [Mapping AVEN.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ARID4A (14q23.1) / AVEN (15q14)EIF2AK4 (15q15.1) / AVEN (15q14)


Description The human AVEN gene is located on the reverse strand of chromosome 15 (bases 34158428 to 34331303; according to NCBI RefSeq gene database (gene ID: 57099; Refseq ID: NM_020371.2), genome assembly GRCh37 from February 2009) of the human genome and is comprised of 172876 bp. AVEN consists of 6 exons, ranging in length between 70 and appr. 500 bp and 5 introns varying largely in size (from few 100 bp to some Mb). According to the Ensembl genome browser database (ENSG00000169857), there are three transcript variants of AVEN of which only one leads to the translation of a functional protein whereas the other two are degraded by nonsense-mediated decay or do not encode for a functional protein product.
Transcription According to the NCBI database, the human AVEN gene encodes for a 1551 bp mRNA transcript, the coding sequence ranging from bp 57 to 1145. The CDS in the Ensembl genome browser database (ENSG00000169857) is identical to the NCBI CDS (NM_020371.2). The transcript NM_020371.2 is also included in the human CCDS set and encodes for a protein of 362 aa.
Pseudogene None known.

3. Protein

  AVEN protein: 1-362 aa. Cathepsin D cleavage sites: L144 and L196; putative BH3 domain: aa141-153; NES: aa282-293. ATM kinase phosphorylation sites: S 135 and S 308.
Description The AVEN protein possesses no predicted domains according to the NCBI database. However, a sequential proteolytic processing of AVEN by the lysosomal protease cathepsin D has been published (Melzer et al., 2012), leading to the cleavage of AVEN at aa 144 and 196 and the generation of a shorter isoform (deltaN Aven) that is supposed to be associated with the antiapoptotic function. Moreover, AVEN is able to bind to the DNA damage response regulating kinase ATM (ataxia telangiectasia mutated) and is phosphorylated by ATM at S135 and S308 (Guo et al., 2008). In addition, a potential nuclear export sequence (NES) to exists between aa 282-293 (Esmaili et al., 2010) and a putative BH3 motif (for binding to Bcl-xL) has been predicted to be located between aa 141-153 (Hawley et al., 2012).
Expression Widely expressed throughout the human organism (Chau et al., 2000).
Localisation Mostly cytosolic, punctuate, reticular pattern (associated with intracellular membrane localization, lysosomal?) in the cytosol (Chau et al., 2000), diffuse nuclear staining (Esmaili et al., 2010).
Function Antiapoptotic:
AVEN was first discovered as an interactor of the antiapoptotic BCl-xL protein by Chau et al. (2000). It was also shown to bind to the proapoptotic APAF-1 protein and postulated to prevent the oligomerization of APAF-1 (apoptosome formation) in the intrinsic apoptosis pathway and to stabilize the Bcl-xL protein by binding to it (Kutuk et al., 2010). Putative binding sites in Bcl-xL are predicted to be located in the Bcl-xL BH1 and BH4 domains (Hawley et al., 2012). Recently, it was shown that AVEN can be processed by the lysosomal protease Cathepsin D at aa 144 and 196, and that this processing is neccessary to activate AVEN's antiapoptotic function (Melzer et al., 2012). It is still unclear whether it is the stabilization of Bcl-xL, the interference with apoptosome assembly or another feature of AVEN that is responsible for the antiapoptotic capacity of this protein.

DNA damage repair:
It was shown by Guo et al. (2008) that AVEN, in addition to binding to the apoptotic machinery, is also able to bind one of the key players in DNA damage repair, the ataxia telangiectasia mutated (ATM) kinase. Overexpression of AVEN in Xenopus laevis egg extracts induced a cell cycle arrest at G2/M which is in large part ATM dependent, whereas the absence of AVEN impaired ATM-mediated checkpoint function. An intrinsic loop of activation exists between AVEN and ATM: AVEN binds to the kinase domain of ATM (appr. aa 2500-3000) and, in turn, is phosphorylated by ATM at S135 and S308. This phosphorylation seems to enhance AVEN's activating influence on ATM. Esmaili et al. (2010) were able to demonstrate that AVEN possesses a nuclear export signal (NES) which is located between aa 282 and 293. Under normal physiological conditions, AVEN is shuttled outside of the nucleus by Exportin-1/CRM1 whereas inhibition of CRM1 by leptomycin or mutation of the AVEN NES leads to nuclear accumulation of the protein. The NES/nuclear-cytosolic shuttling of AVEN might be important for its cell cycle regulatory functions and its role in DNA damage repair.
Depending on the degree of DNA damage, AVEN is possibly a multifunctional protein, finetuning the cellular decisions of cell cycle arrest and apoptosis in the DNA damage response.

Homology No close orthologs of AVEN in humans are known. However, Hawley et al. (2010) note homology to Bik (58% homology over a 77 aa region encompassing the putative BH3 homology domain).
Homologs of AVEN can be found in several species, like mouse (NCBI acc. Nr. NP_083120), Drosophila (NP_572817), rat (NP_001101227), chicken (NP_001005791; Vezyri et al., 2011) and Xenopus (NP_001090621; Guo et al., 2008). Of note, two isoforms are postulated to exist in mouse, the second one (NP_001159407) possessing a distinctly shorter N-terminus than the full length protein. However, nothing is known about the function or biological relevance of this predicted second isoform. Functional similarity to the human protein in its cell cycle regulatory properties has been published for the Drosophila (Zou et al., 2011) and the Xenopus homologs (Guo et al., 2008).

4. Implicated in

Entity Acute leukemias
Note AVEN is a putative oncogene which is overexpressed in T- cell acute lymphoblastic leukemia.
First reports that AVEN is overexpressed on mRNA level in acute leukemias were published by Paydas et al. in 2003. The authors investigated a study group consisting of 37 acute myeloblastic leukemias (AML) and 28 acute lymphoblastic leukemia (ALL) patients. Details regarding the number of ALL patients who were either of the frequent B-cell type or had developed T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) were not given. In this study, elevated Aven mRNA expression levels were noted in acute leukemias, and the authors suggest that AVEN could be a new prognostic marker in this cancer entity. Choi et al. (2006) describe a positive correlation between Aven mRNA overexpression and poor prognosis in childhood ALL.
A recent study by Eissmann et al. (2013) shows proof that overexpression of AVEN contributes to increased malignancy in hematopoietic neoplasms. Here, the authors confirm overexpression of AVEN in T-ALL patient samples compared to healthy T cells on protein level. Furthermore, using a transgenic mouse model with T-cell specific overexpression of AVEN, an oncogenic cooperation of AVEN with heterozygous loss of p53 is shown. Additionally, in subcutaneous mouse xenograft models, the authors show that downregulation of AVEN expression via shRNA leads to significantly decreased, if not halted, tumor growth indicating AVEN as a putative novel therapy target for T-ALL and AML.
Entity Breast cancer
Note Two other studies implicate AVEN in breast cancer (Kutuk et al., 2010; Ouzounova et al., 2013).
Kutuk et al. describe decreased nuclear expression of AVEN in breast cancer tissue microarrays, in particular in infiltrative ductal carcinoma and papillary carcinoma compared to non-neoplastic breast tissue and infiltrating lobular breast cancer. They suggest that AVEN might be an important mediator in DNA damage-induced apoptotic signalling and its nuclear downregulation in breast cancer can lead to genomic instability. A recent study by Ouzounova et al. shows that AVEN is an inversely regulated downstream target of the miR-30 family which is important for regulation of breast cancer cells under non-attachment conditions. Overexpression of miR-30 family members reduces breast tumor progression and tumorsphere formation (and AVEN expression), an effect which could be partially rescued by AVEN re-/overexpression, suggesting, in contrast to the other study, that rather overexpression (than downregulation or nuclear depletion) of AVEN is important for breast tumor growth.

5. Bibliography

Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1.
Chau BN, Cheng EH, Kerr DA, Hardwick JM.
Mol Cell. 2000 Jul;6(1):31-40.
PMID 10949025
Aven overexpression: association with poor prognosis in childhood acute lymphoblastic leukemia.
Choi J, Hwang YK, Sung KW, Kim DH, Yoo KH, Jung HL, Koo HH.
Leuk Res. 2006 Aug;30(8):1019-25. Epub 2006 Jan 18.
PMID 16388850
Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms.
Eissmann M, Melzer IM, Fernandez SB, Michel G, Hrabe de Angelis M, Hoefler G, Finkenwirth P, Jauch A, Schoell B, Grez M, Schmidt M, Bartholomae CC, Newrzela S, Haetscher N, Rieger MA, Zachskorn C, Mittelbronn M, Zornig M.
Oncogene. 2013 May 16;32(20):2586-91. doi: 10.1038/onc.2012.263. Epub 2012 Jul 2.
PMID 22751129
Regulation of the ATM-activator protein Aven by CRM1-dependent nuclear export.
Esmaili AM, Johnson EL, Thaivalappil SS, Kuhn HM, Kornbluth S, Irusta PM.
Cell Cycle. 2010 Oct 1;9(19):3913-20. Epub 2010 Oct 25.
PMID 20935510
Aven-dependent activation of ATM following DNA damage.
Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S.
Curr Biol. 2008 Jul 8;18(13):933-42. doi: 10.1016/j.cub.2008.05.045. Epub 2008 Jun 19.
PMID 18571408
An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates.
Hawley RG, Chen Y, Riz I, Zeng C.
Open Biol J. 2012 May 4;5:6-16.
PMID 22754595
Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL.
Kutuk O, Temel SG, Tolunay S, Basaga H.
Eur J Cancer. 2010 Sep;46(13):2494-505. doi: 10.1016/j.ejca.2010.06.011. Epub 2010 Jul 7.
PMID 20619636
The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential.
Melzer IM, Fernandez SB, Bosser S, Lohrig K, Lewandrowski U, Wolters D, Kehrloesser S, Brezniceanu ML, Theos AC, Irusta PM, Impens F, Gevaert K, Zornig M.
Cell Death Differ. 2012 Sep;19(9):1435-45. doi: 10.1038/cdd.2012.17. Epub 2012 Mar 2.
PMID 22388353
MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells.
Ouzounova M, Vuong T, Ancey PB, Ferrand M, Durand G, Le-Calvez Kelm F, Croce C, Matar C, Herceg Z, Hernandez-Vargas H.
BMC Genomics. 2013 Feb 28;14:139. doi: 10.1186/1471-2164-14-139.
PMID 23445407
Survivin and aven: two distinct antiapoptotic signals in acute leukemias.
Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B, Burgut R.
Ann Oncol. 2003 Jul;14(7):1045-50.
PMID 12853345
Molecular cloning and expression of Aven gene in chicken.
Vezyri E, Mikrou A, Athanassiadou A, Zarkadis IK.
Protein J. 2011 Jan;30(1):72-6. doi: 10.1007/s10930-011-9304-6.
PMID 21234663
Identification of dAven, a Drosophila melanogaster ortholog of the cell cycle regulator Aven.
Zou S, Chang J, LaFever L, Tang W, Johnson EL, Hu J, Wilk R, Krause HM, Drummond-Barbosa D, Irusta PM.
Cell Cycle. 2011 Mar 15;10(6):989-98. Epub 2011 Mar 15.
PMID 21368576

6. Citation

This paper should be referenced as such :
Melzer, IM ; Z_rnig, M
AVEN (apoptosis, caspase activation inhibitor)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):311-313.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/AVENID43158ch15q14.html

7. Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]

  t(14;15)(q23;q14) ARID4A/AVEN

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(15;15)(q14;q15) EIF2AK4/AVEN

8. External links

HGNC (Hugo)AVEN   13509
Entrez_Gene (NCBI)AVEN  57099  apoptosis and caspase activation inhibitor
GeneCards (Weizmann)AVEN
Ensembl hg19 (Hinxton)ENSG00000169857 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000169857 [Gene_View] &nbspENSG00000169857 [Sequence]  chr15:33866227-34039102 [Contig_View]  AVEN [Vega]
ICGC DataPortalENSG00000169857
Genatlas (Paris)AVEN
SOURCE (Princeton)AVEN
Genetics Home Reference (NIH)AVEN
Genomic and cartography
GoldenPath hg38 (UCSC)AVEN  -     chr15:33866227-34039102 -  15q14   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)AVEN  -     15q14   [Description]    (hg19-Feb_2009)
EnsemblAVEN - 15q14 [CytoView hg19]  AVEN - 15q14 [CytoView hg38]
Mapping of homologs : NCBIAVEN [Mapview hg19]  AVEN [Mapview hg38]
Gene and transcription
Genbank (Entrez)AF283508 AK025888 BC010488 BC063533 BU855198
RefSeq transcript (Entrez)NM_020371
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)AVEN
Cluster EST : UnigeneHs.555966 [ NCBI ]
CGAP (NCI)Hs.555966
Alternative Splicing GalleryENSG00000169857
Gene ExpressionAVEN [ NCBI-GEO ]   AVEN [ EBI - ARRAY_EXPRESS ]   AVEN [ SEEK ]   AVEN [ MEM ]
Gene Expression Viewer (FireBrowse)AVEN [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets] &nbsp [Normal Tissue Atlas] &nbsp[carcinoma Classsification] &nbsp[NCI60]
GenevestigatorExpression in : [tissues] &nbsp[cell-lines] &nbsp[cancer] &nbsp[perturbations] &nbsp
BioGPS (Tissue expression)57099
GTEX Portal (Tissue expression)AVEN
Human Protein AtlasENSG00000169857-AVEN [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NQS1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NQS1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NQS1
Splice isoforms : SwissVarQ9NQS1
Domains : Interpro (EBI)Aven   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)AVEN
DMDM Disease mutations57099
Blocks (Seattle)AVEN
Human Protein Atlas [tissue]ENSG00000169857-AVEN [tissue]
Peptide AtlasQ9NQS1
Protein Interaction databases
IntAct (EBI)Q9NQS1
Ontologies - Pathways
Ontology : AmiGOprotein binding  apoptotic process  endomembrane system  membrane  negative regulation of apoptotic process  
Ontology : EGO-EBIprotein binding  apoptotic process  endomembrane system  membrane  negative regulation of apoptotic process  
NDEx NetworkAVEN
Atlas of Cancer Signalling NetworkAVEN
Wikipedia pathwaysAVEN
Orthology - Evolution
GeneTree (enSembl)ENSG00000169857
Phylogenetic Trees/Animal Genes : TreeFamAVEN
Homologs : HomoloGeneAVEN
Homology/Alignments : Family Browser (UCSC)AVEN
Gene fusions - Rearrangements
Fusion : MitelmanEIF2AK4/AVEN [15q15.1/15q14] &nbsp[t(15;15)(q14;q15)]  
Fusion PortalEIF2AK4 15q15.1 AVEN 15q14 LUAD
Fusion : QuiverAVEN
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerAVEN [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)AVEN
Exome Variant ServerAVEN
ExAC (Exome Aggregation Consortium)ENSG00000169857
GNOMAD BrowserENSG00000169857
Varsome BrowserAVEN
Genetic variants : HAPMAP57099
Genomic Variants (DGV)AVEN [DGVbeta]
DECIPHERAVEN [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisAVEN 
ICGC Data PortalAVEN 
TCGA Data PortalAVEN 
Broad Tumor PortalAVEN
OASIS PortalAVEN [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICAVEN  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDAVEN
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch AVEN
DgiDB (Drug Gene Interaction Database)AVEN
DoCM (Curated mutations)AVEN (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)AVEN (select a term)
NCG5 (London)AVEN
Cancer3DAVEN(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry AVEN
NextProtQ9NQS1 [Medical]
Target ValidationAVEN
Huge Navigator AVEN [HugePedia]
snp3D : Map Gene to Disease57099
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD57099
Chemical/Pharm GKB GenePA134874337
Clinical trialAVEN
canSAR (ICR)AVEN (select the gene name)
DataMed IndexAVEN
PubMed27 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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