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APAF1 (Apoptotic protease activating factor 1)

Written2004-09Marco Corvaro, Francesco Cecconi
Dulbecco Telethon Institute,Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_namesapoptotic protease activating factor
apoptotic peptidase activating factor
Alias_symbol (synonym)CED4
APAF-1
Other aliasKIAA0413
Apaf-1
HGNC (Hugo) APAF1
LocusID (NCBI) 317
Atlas_Id 422
Location 12q23.1  [Link to chromosome band 12q23]
Location_base_pair Starts at 98645300 and ends at 98735433 bp from pter ( according to hg19-Feb_2009)  [Mapping APAF1.png]
Local_order
  • solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3 12q23
  • IKK interacting protein 12q23.1
  • APAF1 12q23
  • E2a-Pbx1-associated protein / EB1 12q23.1-q23.2
    		•
    Fusion genes
    (updated 2017)    		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
    APAF1 (12q23.1) / TLN1 (9p13.3)APAF1 (12q23.1) / UNC13B (9p13.3)

    DNA/RNA

    Description The APAF1 gene is comprised of 27 exons, with the coding region spanning 26 exons (the ATG is in the second exon
    Transcription Five isoforms of APAF1 cDNA have been identified in Homo sapiens
  • the original APAF1 (also called Apaf-1S) is 3585 bp long (it contains 12 WD40 repeats);
  • the APAF1-1M isoform (3618 bp) contains an insertion of 33 nt after position 295 of the first published sequence (11 aa insertion GKDSVSGITSY between aa 98 and 99; it also contains 12 WD40 repeats);
  • the APAF1XS isoform (3516 bp) contains the same insertion of Apaf-1M form, lacks the base pairs from 3171 to 3296 of the Apaf-1S form (the deletion is in WD40 domain) but has an insertion of 24 nt at position 1725
  • the APAF1L (3714 bp) contains an insertion of 129 nt at position 2466(contains 13 WD40 repeats);
  • the APAF1XL (3747 bp)isoform contains the same insertion of APAF1M form, plus and additional insertion of 129 bp (43 aa beetween aa 811-812; Apaf-1XL also contains 13 WD40 repeats);
    • Pseudogene not known

    Protein

     
      Figure 1: The conformational changes in the APAF1 molecules lead to apoptosome formation and to the activation of apoptosis. However, the assembly and the functioning of the apoptosome is regulated by mithocondrial and cytosolic factors (modif. from E. Ferraro et al. 2004)
    Description the protein can be divided into three domains: the N-terminal is a CARD domain and is necessary for APAF1 function; alternatively, it can bind the WD40 domain or cytochrome C. The ced-4-like domain is responsible for APAF1 conformational changes. The C-terminal WD40 domain is a negative regulator element composed of 12 or 13 WD40 repeats: it can bind the CARD domain but it can probably interact with other apoptotic regulator proteins as well.
    Expression APAF1 Promoter can interact with E2F1 (also E2F2-3) and p53 which can in turn regulate its expression.
    Localisation cytosolic
    Function APAF1 is the structural core of the apoptosome. When the mitochondrial pathway of apoptosis is activated, cytochrome c is released from mitochondria to cytosol, and then binds to APAF1 CARD domain changing its conformation. A further binding of ATP molecules mediates a second conformational change which leads to open APAF1 conformation. By means of the CARD domain, seven APAF1 molecules bind to each other and to seven molecules of initiator Caspase-9 forming the apoptosome and causing the activation of effector caspases. The formation of apoptosome and the activation of caspases are regulated by numerous interacting proteins.
    Homology CED-4 (C. elegans); DARK (D. melanogaster); CARD proteins.

    Mutations

    Germinal not known in H. sapiens.
    Somatic not known in H. sapiens.

    Implicated in

    Note
      
    Entity Skin Cancers ( Melanoma, Basal Cell Carcinoma, Squamous Cell Carcinoma).
    Cytogenetics Frequent LOH in 12q22-23 locus (primary melanomas: 20-25% metastatic melanomas 35-40%).
    Oncogenesis The silencing of Apaf1 expression is often found in Melanomas. Two main mechanisms have been posited for APAF1 dimininution, either the allelic LOH in 12q22-23 locus and/or a transcriptional silencing by promoter methylation. The inactivation was not found in Nevi but it increased significantly in the later stages of carcinogenesis, when primary melanomas are fully developed (1-3mm of diameter). Very often such inactivation was associated with metastatic melanomas. Moreover, the APAF1 level is correlated with chemosensivity to different agents; different studies demonstrate that overexpressing or restoring a normal APAF1 level could sensitize chemoresistant melanoma cell lines, in vitro. Recently, APAF1 LOH determination on blood serum DNA has been proposed as a marker for selecting appropriate chemotherapy in stage IV melanoma patients.
      
      
    Entity Brain tumors (neural tumors, glial tumors)
    Cytogenetics Frequent LOH in 12q22-23 locus in glioblastomas (40%)
    Oncogenesis APAF1 seems to be downregulated or absent in Glioblastomas at mRNA and protein level. In addition, the co-overexpression of APAF1 and Caspase-9 sensitizes glioma cell lines (U-251 and U-373 MG) to p53-dependent apoptosis. Other modulations of the apoptosome-related apoptosis have been successfully conducted in order to induce apoptosis in glioma resistant lines. By contrast, APAF1 seems to be active in Neuroblastomas while there are no studies about a putative APAF1 role in other glial tumors (such as ependimoma, astrocytoma, ganglioglioma).
      
      
    Entity Head and neck cancers and odontogenic tumors.
    Oncogenesis There is no direct evidence of APAF1's role in the oncogenesis of these types of cancer even though Apaf1 loss has been correlated with gain of Cisplatin Chemoresistance in HSC-2CR cells (derived from HSC-2 head squamous carcinoma cells).
      
      
    Entity Gastro-intestinal tract cancers ( oesophagus cancer, gastric cancer, gallbladder cancer, ampulla of vater cancer, peritoneum cancer, vermiform appendix cancer, colon cancer, rectal cancer, cancer of the anus).
    Oncogenesis A low frequency of mutations (10-15 % of cases) is found in ColoRectal and Gastric Cancer. these mutations are due to the genetics of microsatellite instability and appear to be heterozygous. No evidences of APAF1 involvement have been found in the pathogenesis of the other tumors mentioned
      
      
    Entity Exocrinus pancreas cancers (various stages of the pancreas ductal adenocarcinoma - PDAC)
    Cytogenetics 12q 1ocus deletions could be considered among the most frequent deletions in PDAC.
    Oncogenesis There is no direct evidence of APAF1 mutations in the progression of the PDAC (some even deny its possible role completely). There are many studies, however, which point out the 12q22-23 locus LOH or mutation in PDAC. Most of the mutated genes involved (such as K-Ras, p53, p16INK4a, p19ARF) can control the APAF1 level directly or indirectly throught the action of p53 and E2F-1 which both have active binding boxes to the APAF1 promoter.
      
      
    Entity Liver cancer and liver metastases
    Oncogenesis Methylation is a common feature in hepatocellular carcinoma (HCC) regulation. While the analysis of promoters methylation in HCC samples showed that the APAF1 gene is not hypermethylated, the HepG2 cells exposed to a demethylating agent (DEM, diethyl maleate) showed an increased level of Apaf1 and of some caspases which lead to G2 phase arrest and apoptosis.
      
      
    Entity Lung cancer
    Oncogenesis There is no direct evidence for abrogation of APAF1 function in lung cancer. However, the APAF1/Caspase-9 upregulation seem to be a protective mechanism in some NSCLC ( non small cell lung carcinoma) cell lines, while in other NSCLC lines (such as the NCI-H460) an indirect APAF1 loss of function is mediated by the upregulation of XIAP (an inhibitor of Apoptosome assembly). Furthermore, a driven expression of APAF1/ Caspase-9 (through the Inibition of XIAP in NCI-H460 cells or with low dose lung cancer cell lines) seems to augment sensitivity to death.
      
      
    Entity Tumors of the female reproductive organs ( ovarian carcinoma, neoplasms of Fallopian tube, endometrium, cervix, vulva and vagina)
    Oncogenesis In ovarian carcinoma, the APAF1 gene seems to be active. However, dysfunction in the apoptosome assembly process has been correlated with chemoresistance. In contrast, loss of heterozygosity was found in the apaf1 locus in malignant ovarian germ cell tumors. There is no information about the reproductive tract.
      
      
    Entity Tumors of the male reproductive organs ( seminoma, nonseminomatous germ cell tumors, sex cord-stromal tumors , other testis cancers, neoplasms of prostate, tumor of the penis)
    Cytogenetics Frequent deletions in Chromosome 12 long and short arm in germ line tumors; LOH in 12q22-23 is present in seminomas, non-seminomatous tumors and in mixed teratomas with various reported percentage (20-45%)
    Oncogenesis In Germ line tumors the APAF1 locus is often deleted; however it seems that APAF1 level was normal in various analyzed lines. Interestingly, Cisplatin treatment of a embryonal carcinoma cell line, TTSC-3 lead to the differentiation of the carcinoma through the up-regulation of pro-differentiation and pro-apoptotic genes (such as APAF1, Caspase-8 and TNFR1). In Prostatic Tumor there is no evidence of APAF1 involvement; however some studies have been conducted demontrating an increase of Apaf1 at transcription level as a cellular response to chemotherapeutic agents.
      
      
    Entity Urinary tract tumors ( renal cell carcinoma, neoplasms of the renal pelvis, ureter, bladder, urethra)
    Oncogenesis The Apoptosome function seems to be active in primary samples and in a few cell lines of Renal Cell Carcinoma. There are no informations about the urinary tract.
      
      
    Entity Hematopoietic system tumors.
    Oncogenesis It's not clear if APAF1 gene is corrupted in Leukaemias and Lymphomas. However, while the methylation of the promoter was demonstrated in different kinds of leukaemia, the protein level does not correlate with the messenger level, suggesting a multistep regulation in APAF1 expression. Furthermore, it has been demonstrated that the APAF1 overexpression, conducted by in vitro transfection or by chemoadiuvants, could overcome the resistance to chemo-radiotherapeutic agents.
      
      
    Entity Bone and soft tissue cancers (osteoma, sarcoma, fibroma, osteosarcoma)
    Oncogenesis There is no direct evidence of APAF1 role in the oncogenesis of these types of cancer even though in Ewing's sarcoma cell lines the Apaf1 low level found in two different lines (STA-ET-2.1 and STA-ET-2.2) was correlated with chemoresistance to p53-dependent death stimuli compared with lines with normal APAF1 level. APAF1 was also absent and correlated with chemoresistance in the HT-1080 fibrosacroma cell line.
      
      
    Entity Various tumors ( eye tumor, heart and great vessels tumors, neoplasm of the endocrine glands and of the diffuse endocrine system, tumor of mesotheliums)
    Oncogenesis At present, there is no direct evidence of APAF1 involvement in the carcinogenesis of these neoplasms.
      

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    Citation

    This paper should be referenced as such :
    Corvaro, M ; Cecconi, F
    APAF1 (apoptotic protease activating factor 1)
    Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):289-293.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/APAF1ID422.html

    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
      Lung: Translocations in Adenocarcinoma
    t(9;12)(p13;q23) APAF1/TLN1
    t(9;12)(p13;q23) APAF1/UNC13B

    External links

    Nomenclature
    HGNC (Hugo)APAF1   576
    Cards
    AtlasAPAF1ID422
    Entrez_Gene (NCBI)APAF1  317  apoptotic peptidase activating factor 1
    AliasesAPAF-1; CED4
    GeneCards (Weizmann)APAF1
    Ensembl hg19 (Hinxton)ENSG00000120868 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000120868 [Gene_View]  ENSG00000120868 [Sequence]  chr12:98645300-98735433 [Contig_View]  APAF1 [Vega]
    ICGC DataPortalENSG00000120868
    TCGA cBioPortalAPAF1
    AceView (NCBI)APAF1
    Genatlas (Paris)APAF1
    WikiGenes317
    SOURCE (Princeton)APAF1
    Genetics Home Reference (NIH)APAF1
    Genomic and cartography
    GoldenPath hg38 (UCSC)APAF1  -     chr12:98645300-98735433 +  12q23.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)APAF1  -     12q23.1   [Description]    (hg19-Feb_2009)
    EnsemblAPAF1 - 12q23.1 [CytoView hg19]  APAF1 - 12q23.1 [CytoView hg38]
    Mapping of homologs : NCBIAPAF1 [Mapview hg19]  APAF1 [Mapview hg38]
    OMIM602233   
    Gene and transcription
    Genbank (Entrez)AB007873 AB103079 AF013263 AF134397 AF149794
    RefSeq transcript (Entrez)NM_001160 NM_013229 NM_181861 NM_181868 NM_181869
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)APAF1
    Cluster EST : UnigeneHs.552567 [ NCBI ]
    CGAP (NCI)Hs.552567
    Alternative Splicing GalleryENSG00000120868
    Gene ExpressionAPAF1 [ NCBI-GEO ]   APAF1 [ EBI - ARRAY_EXPRESS ]   APAF1 [ SEEK ]   APAF1 [ MEM ]
    Gene Expression Viewer (FireBrowse)APAF1 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)317
    GTEX Portal (Tissue expression)APAF1
    Human Protein AtlasENSG00000120868-APAF1 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtO14727   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtO14727  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProO14727
    Splice isoforms : SwissVarO14727
    PhosPhoSitePlusO14727
    Domaine pattern : Prosite (Expaxy)CARD (PS50209)    WD_REPEATS_1 (PS00678)    WD_REPEATS_2 (PS50082)    WD_REPEATS_REGION (PS50294)   
    Domains : Interpro (EBI)Apaf-1    APAF1_CARD_dom    CARD    DEATH-like_dom_sf    G-protein_beta_WD-40_rep    NB-ARC    P-loop_NTPase    WD40/YVTN_repeat-like_dom_sf    WD40_repeat    WD40_repeat_CS    WD40_repeat_dom    WD40_repeat_dom_sf    WH-like_DNA-bd_sf   
    Domain families : Pfam (Sanger)CARD (PF00619)    NB-ARC (PF00931)    WD40 (PF00400)   
    Domain families : Pfam (NCBI)pfam00619    pfam00931    pfam00400   
    Domain families : Smart (EMBL)WD40 (SM00320)  
    Conserved Domain (NCBI)APAF1
    DMDM Disease mutations317
    Blocks (Seattle)APAF1
    PDB (SRS)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    PDB (PDBSum)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    PDB (IMB)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    PDB (RSDB)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    Structural Biology KnowledgeBase1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    SCOP (Structural Classification of Proteins)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    CATH (Classification of proteins structures)1C15    1CWW    1CY5    1Z6T    2P1H    2YGS    3J2T    3JBT    3YGS    4RHW    5JUY    5WVC    5WVE   
    SuperfamilyO14727
    Human Protein Atlas [tissue]ENSG00000120868-APAF1 [tissue]
    Peptide AtlasO14727
    HPRD03755
    IPIIPI00023630   IPI00217460   IPI00217461   IPI00217462   IPI00217463   IPI00375875   IPI00953387   IPI01021762   
    Protein Interaction databases
    DIP (DOE-UCLA)O14727
    IntAct (EBI)O14727
    FunCoupENSG00000120868
    BioGRIDAPAF1
    STRING (EMBL)APAF1
    ZODIACAPAF1
    Ontologies - Pathways
    QuickGOO14727
    Ontology : AmiGOnucleotide binding  response to hypoxia  kidney development  neural tube closure  protein binding  ATP binding  extracellular region  nucleus  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  nervous system development  aging  response to nutrient  activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c  activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c  cysteine-type endopeptidase activator activity involved in apoptotic process  cysteine-type endopeptidase activator activity involved in apoptotic process  cardiac muscle cell apoptotic process  cell differentiation  forebrain development  heat shock protein binding  protein-containing complex  secretory granule lumen  identical protein binding  regulation of apoptotic process  positive regulation of apoptotic process  apoptosome  apoptosome  apoptosome  neutrophil degranulation  ADP binding  protein homooligomerization  neuron apoptotic process  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  extracellular exosome  negative regulation of G0 to G1 transition  cellular response to transforming growth factor beta stimulus  response to G1 DNA damage checkpoint signaling  intrinsic apoptotic signaling pathway  regulation of apoptotic DNA fragmentation  ficolin-1-rich granule lumen  positive regulation of apoptotic signaling pathway  
    Ontology : EGO-EBInucleotide binding  response to hypoxia  kidney development  neural tube closure  protein binding  ATP binding  extracellular region  nucleus  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  nervous system development  aging  response to nutrient  activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c  activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c  cysteine-type endopeptidase activator activity involved in apoptotic process  cysteine-type endopeptidase activator activity involved in apoptotic process  cardiac muscle cell apoptotic process  cell differentiation  forebrain development  heat shock protein binding  protein-containing complex  secretory granule lumen  identical protein binding  regulation of apoptotic process  positive regulation of apoptotic process  apoptosome  apoptosome  apoptosome  neutrophil degranulation  ADP binding  protein homooligomerization  neuron apoptotic process  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  extracellular exosome  negative regulation of G0 to G1 transition  cellular response to transforming growth factor beta stimulus  response to G1 DNA damage checkpoint signaling  intrinsic apoptotic signaling pathway  regulation of apoptotic DNA fragmentation  ficolin-1-rich granule lumen  positive regulation of apoptotic signaling pathway  
    Pathways : KEGGp53 signaling pathway    Apoptosis    Alzheimer's disease    Parkinson's disease    Amyotrophic lateral sclerosis (ALS)    Huntington's disease    Legionellosis    Tuberculosis    Hepatitis B    Small cell lung cancer   
    REACTOMEO14727 [protein]
    REACTOME PathwaysR-HSA-8953750 [pathway]   
    NDEx NetworkAPAF1
    Atlas of Cancer Signalling NetworkAPAF1
    Wikipedia pathwaysAPAF1
    Orthology - Evolution
    OrthoDB317
    GeneTree (enSembl)ENSG00000120868
    Phylogenetic Trees/Animal Genes : TreeFamAPAF1
    HOVERGENO14727
    HOGENOMO14727
    Homologs : HomoloGeneAPAF1
    Homology/Alignments : Family Browser (UCSC)APAF1
    Gene fusions - Rearrangements
    Fusion : MitelmanAPAF1/TLN1 [12q23.1/9p13.3]  
    Fusion : MitelmanAPAF1/UNC13B [12q23.1/9p13.3]  [t(9;12)(p13;q23)]  
    Fusion : QuiverAPAF1
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerAPAF1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)APAF1
    dbVarAPAF1
    ClinVarAPAF1
    1000_GenomesAPAF1 
    Exome Variant ServerAPAF1
    ExAC (Exome Aggregation Consortium)ENSG00000120868
    GNOMAD BrowserENSG00000120868
    Varsome BrowserAPAF1
    Genetic variants : HAPMAP317
    Genomic Variants (DGV)APAF1 [DGVbeta]
    DECIPHERAPAF1 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisAPAF1 
    Mutations
    ICGC Data PortalAPAF1 
    TCGA Data PortalAPAF1 
    Broad Tumor PortalAPAF1
    OASIS PortalAPAF1 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICAPAF1  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDAPAF1
    intOGen PortalAPAF1
    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 APAF1
    DgiDB (Drug Gene Interaction Database)APAF1
    DoCM (Curated mutations)APAF1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)APAF1 (select a term)
    intoGenAPAF1
    NCG5 (London)APAF1
    Cancer3DAPAF1(select the gene name)
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM602233   
    Orphanet
    DisGeNETAPAF1
    MedgenAPAF1
    Genetic Testing Registry APAF1
    NextProtO14727 [Medical]
    TSGene317
    GENETestsAPAF1
    Target ValidationAPAF1
    Huge Navigator APAF1 [HugePedia]
    snp3D : Map Gene to Disease317
    BioCentury BCIQAPAF1
    ClinGenAPAF1
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD317
    Chemical/Pharm GKB GenePA24868
    Clinical trialAPAF1
    Miscellaneous
    canSAR (ICR)APAF1 (select the gene name)
    Probes
    Litterature
    PubMed176 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineAPAF1
    EVEXAPAF1
    GoPubMedAPAF1
    iHOPAPAF1
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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