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CASP8AP2 (caspase 8 associated protein 2)

Written2015-03Rocío Juárez-Velázquez, Patricia Pérez-Vera
Laboratorio de Cultivo de Tejidos, Departamento de Genética Humana, Instituto Nacional de Pediatria, Mexico, Mexico; pperezvera@yahoo.com

Abstract CASP8AP2 was initially identified as a pro-apoptotic protein that transmits an apoptosis indication through the death-inducing signaling complex. More recently, diverse functions have been described including TNF-induced NF-kappaB activation, cell-cycle progression and cell division, regulation of histone gene transcription and histone mRNA processing.

Keywords CASP8AP2

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCASP8 associated protein 2
Alias_symbol (synonym)FLASH
CED-4
RIP25
FLJ11208
KIAA1315
Other aliasCASP8 associated protein
FLICE-associated huge protein
HGNC (Hugo) CASP8AP2
LocusID (NCBI) 9994
Atlas_Id 926
Location 6q15 ; CASP8AP2 gene is located on the long arm of chromosome 6 NC_000006.12, in opposite orientation  [Link to chromosome band 6q15]
Location_base_pair Starts at 89829900 and ends at 89874436 bp from pter ( according to hg19-Feb_2009)  [Mapping CASP8AP2.png]
Fusion genes
(updated 2016)
KMT2A (11q23.3) / CASP8AP2 (6q15)PPIG (2q31.1) / CASP8AP2 (6q15)

DNA/RNA

 
  Genomic location and gene products of CASP8AP2. The gene is located at 6q15, it has three transcripts, and all of them encode the same protein.
Description 44,537 bp; 10 exons
Transcription : Three transcripts reported at NCBI: Variant1, 6,821bp NM_012115.3; Variant2, 6,782bp NM_001137667.1; Variant3, 6,649bp NM_001137668.1. Alternative splicing results in multiple transcript variants encoding the same protein.

Protein

Description Size 1982 amino acids; 222,658 kDa protein. It contains a motif structurally related to CED4/Apaf1 (602233) and a C-terminal death effector domain (DED)-recruiting domain (DRD); a NCOA2-binding domain (position 1709-1982aa); a SUMO interaction motifs: SIM1 (position 1683-1687aa), SIM2 (position 1737-1741aa, SIM3 (position 1794-1798aa) which mediate the binding to polysumoylated substrates. The FLASH activity is regulated by sumoylation (Alm-Kristiansen et al., 2009).
Localisation Nucleus, cytoplasm, mitochondrion
Function Component of the apoptosis signaling pathway required for the activation of CASP8 in Fas-mediated apoptosis (Imai Y et al., 1999).
Component of the machinery required for histone precursor mRNA expression and essential for 3end maturation of histone mRNAs (Barcaroli D et al., 2006; De Cola et al., 2012; Yang XC et al., 2009).
It participates in TNF-alpha-induced blockade of glucocorticoid receptor transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappa-B (Kino and Chrousos, 2003).
It also contributes to cell cycle progression at S phase (Kiriyama et al., 2009; Barcaroli D et al., 2006).
Homology Caenorhabditis elegans protein CED-4; Mus musculus protein FLASH

Implicated in

Note
  
Entity t(6;11)(q15;q23)
Disease Acute myeloid leukemia. A t(6;11)(q15;q23) in a 50-year-old Korean woman with acute myeloid leukemia has been reported (Park TS et al., 2009).
Hybrid/Mutated Gene A MLL/CASP8AP2 fusion was identified by LDI-PCR and sequencing, a rearrangement between MLL (intron 8) and CASP8AP2 (intron 7) was detected at the genomic DNA level. The breakpoint analysis at the transcription level was not performed due to lack of a cDNA specimen
Oncogenesis MLL/CASP8AP2 seems to be related to poor clinical outcome, however, further studies are needed to evaluate prognosis.
  
  
Entity Acute lymphoblastic leukemia
Note CASP8AP2 low expression
Prognosis The clinical significance of CASP8AP2 was first reported by (Flotho C et al., 2006), the differences in its expression levels were significantly associated with early response to treatment and the presence of minimal residual disease (MRD). CASP8AP2 expression was analyzed in 99 children with acute lymphoblastic leukemia (ALL) enrolled in the St. Jude Total Therapy Study XIII protocol. Patients with low levels of expression presented a lower event-free survival and higher incidence of relapse, in contrast to patients with higher expression levels. High expression was associated with greater propensity of leukemic cells to undergo apoptosis. In this study CASP8AP2 was considered as an independent prognostic marker for relapse (Flotho C et al., 2006).
The usefulness of CASP8AP2 expression as a potential marker of response to treatment has been analyzed in leukemic patients from different populations. In a cohort of 39 newly diagnosed ALL children treated with the Beijing Children`s Hospital (BCH)-ALL 2003 protocol, the bone marrow expression of CASP8AP2 at diagnosis resulted a suitable indicator of relapse. In the same study, another cohort of 106 patients enrolled in the Chinese Childrens Leukemia Group (CCLG)-ALL 2008 protocol were also analyzed, patients with low CASP8AP2 expression showed higher relapse rates, lower relapse-free survival and lower overall-survival, in comparison to the higher-expression group (Jiao Y et al., 2012). ).
In an independent study a gene signature of 14 genes, including CASP8AP2 and H2AFZ, was identified (Flotho C et al., 2007); their low expressions were associated to relapse. Based on this result, the expressions of CASP8AP2 and H2AFZ were analyzed in a cohort of 88 ALL Mexican children treated with the Popular Medical Insurance protocols (Juárez-Velázquez R et al., 2014). An increased risk for early relapse in patients with low expression of CASP8AP2 was found, confirming its usefulness as a risk marker; the H2AFZ expression did not showed the same effect. The CASP8AP2 expression was not an independent marker of relapse, but combined characteristics as the low expressions of both genes and high white blood cell count, identified more accurately patients at greater risk of relapse (Juárez-Velázquez R et al., 2014). Although the prognostic value of CASP8AP2 expression as an independent factor is controversial (Yang YL et al., 2010), combined with expressions of other genes such as H2AFZ (Juárez-Velázquez R et al., 2014) and ARS2 (Cui L et al., 2015), could more precisely predict high risk of relapse in ALL. ).
Epigenetic modifications are also related to the down-regulation of CASP8AP2. DNA hypermethylation of the gene promoter was analyzed in 86 children with ALL, treated according to the BCH-2003 and CCLG-2008 protocols. The percentage of methylation of two CpG sites at positions -1189 and -1176 were inversely correlated with mRNA expression. The patients with higher methylation presented MRD and poor treatment outcome. The results suggested that combination of methylation level and MRD might improve current risk stratification (Li ZG et al., 2013). In regard to these findings, it has been demonstrated that methylation of the CASP8AP2 promoter in somatic stem cells and cancer cells increase their resistance to drugs (Lee KD et al., 2012). These data associate this epigenetic modification with the development of drug resistance.
  
  
Entity T-cell acute lymphoblastic leukemia) (T-ALL)
Note A del(6)(q15-q16.1) has been reported in approximately 12% of T-ALL patients. This deletion includes the CASP8AP2 gene, whose mRNA expression was the single most down-regulated gene of all 7 genes located in the deleted region.
Prognosis The lower expression of CASP8AP2 has been also associated to deletions at band 6q15-q16.1, which are often detected in patients with T-ALL (Remke M et al., 2009). These deletions result in down regulation of the gene and poor early response to treatment. In 73 T-cell ALL samples obtained from patients enrolled in the multicenter ALL-BFM 1990, ALL-BFM 1995 and ALL-BFM 2000 protocols, deletion 6q15-q16.1 was associated with unfavorable MRD levels. Although deletion 6q15-q16.1 involves several genes, CASP8AP2 was the single one with a better association between the deletion and the less efficient induction of apoptosis by chemotherapy (Remke M et al., 2009).
Cytogenetics The del(6)(q15-q16.1)comprises 2.54 Mb.
  
  
Entity Diffuse large B-cell lymphomas )( activated B-cell like subtype)
Note Loss of CASP8AP2 in 35% of cases. Imbalance with possible pathogenic relevance (Scholtysik R et al., 2015).
  

Bibliography

 
SUMO modification regulates the transcriptional activity of FLASH.
Alm-Kristiansen AH, Norman IL, Matre V, Gabrielsen OS.
Biochem Biophys Res Commun 2009; 387 (3): 494-499
PMID 19615980
 
FLASH Is Required for Histone Transcription and S-Phase Progression
Barcaroli D, Bongiorno-Borbone L, Terrinoni A, Hofmann TG, Rossi M, Knight RA, Matera AG, Melino G, De Laurenzi V.
Proc Natl Acad Sci U S A 2006; 103 (40): 14808-14812
PMID 17003125
 
Low Expressions of ARS2 and CASP8AP2 Predict Relapse and Poor Prognosis in Pediatric Acute Lymphoblastic Leukemia Patients Treated on China CCLG-ALL 2008 Protocol
Cui L, Gao C, Zhang RD, Jiao Y, Li WJ, Zhao XX, Liu SG, Yue ZX, Zheng HY, Deng GR, Wu MY, Li ZG, Jia HT.
Leuk Res 2015; 39 (2): 115-123
PMID 25530566
 
FLASH Is Essential during Early Embryogenesis and Cooperates with p73 to Regulate Histone Gene Transcription
De Cola A, Bongiorno-Borbone L, Bianchi E, Barcaroli D, Carletti E, Knight RA, Di Ilio C, Melino G, Sette C, De Laurenzi v.
Oncogene 2012; 31 (5): 573-582
PMID 21725362
 
A Set of Genes That Regulate Cell Proliferation Predicts Treatment Outcome in Childhood Acute Lymphoblastic Leukemia
Flotho C, Coustan-Smith E, Pei D,Cheng C, Song G, Pui CH, Downing JR, Campana D.
Blood 2007; 110 (4): 1271-1277
PMID 17456722
 
The CED-4-Homologous Protein FLASH Is Involved in Fas-Mediated Activation of Caspase-8 during Apoptosis
Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, Yonehara S.
Nature 1999; 398 (6730): 777-785
PMID 10235259
 
CASP8AP2 Is a Promising Prognostic Indicator in Pediatric Acute Lymphoblastic Leukemia
Jiao Y, Cui L, Gao C, Li W, Zhao X, Liu S, Wu M, Deng G, Li Z.
Leuk Res 2012; 36 (1): 67-71
PMID 21696825
 
Significance of CASP8AP2 and H2AFZ Expression in Survival and Risk of Relapse in Children with Acute Lymphoblastic Leukemia
Juárez-Velázquez R, Reyes-León A, Salas-Labadèa C, Rivera-Luna R, Velasco-Hidalgo L, López-Hernández G, López-Santiago N, Paredes-Aguilera R, Domènguez-López A, Bernáldez R, Pérez-Vera P.
Leuk Lymphoma 2014; 55 (10): 2305-2311
PMID 24397596
 
Tumor Necrosis Factor Alpha Receptor- and Fas-Associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators
Kino T, Chrousos GP.
J Biol Chem 2003 ; 278 (5): 3023-3029
PMID 12477726
 
Interaction of FLASH with Arsenite Resistance Protein 2 Is Involved in Cell Cycle Progression at S Phase
Kiriyama M, Kobayashi Y, Saito M, Ishikawa F, Yonehara S.
Mol Cell Biol 2009; 29 (17): 4729-4741
PMID 19546234
 
Targeted Casp8AP2 Methylation Increases Drug Resistance in Mesenchymal Stem Cells and Cancer Cells
Lee KD, Pai MY, Hsu CC, Chen CC, Chen YL, Chu PY, Lee CH, Chen LT, Chang JY,Huang TH, Hsiao SH, Leu YW.
Biochem Biophys Res Commun 2012; 422 (4): 578-585
PMID 22595458
 
Hypermethylation of Two CpG Sites Upstream of CASP8AP2 Promoter Influences Gene Expression and Treatment Outcome in Childhood Acute Lymphoblastic Leukemia
Li ZG, Jiao Y, Li WJ, Deng GR, Cui L, Gao C, Zhao XX, Wu MY, Jia HT.
Leuk Res 2013; 37 (10): 1287-1293
PMID 23953914
 
CASP8AP2 Is a Novel Partner Gene of MLL Rearrangement with t(6;11)(q15;q23) in Acute Myeloid Leukemia
Park TS, Lee SG, Song J, Lee KA, Kim J, Choi JR, Lee ST, Marschalek R, Meyer C.
Cancer Genet Cytogenet 2009; 195 (1): 94-95
PMID 19837277
 
High-Resolution Genomic Profiling of Childhood T-ALL Reveals Frequent Copy-Number Alterations Affecting the TGF-Beta and PI3K-AKT Pathways and Deletions at 6q15-16.1 as a Genomic Marker for Unfavorable Early Treatment Response
Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A, Werft W, Breit S, Liu S, Engel F, Wittmann A, Zimmermann M, Stanulla M, Schrappe M, Ludwig WD, Bartram CR, Radlwimmer B, Muckenthaler MU, Lichter P, Kulozik AE.
Blood 2009; 114 (5): 1053-1062
PMID 19406988
 
Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis
Scholtysik R, Kreuz M, Hummel M, Rosolowski M, Szczepanowski M, Klapper W, Loeffler M, Trümper L, Siebert R, Küppers R; Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe.
Int J Cancer 2015; 136(5): 1033-1042.
PMID 25042405
 
FLASH, a Proapoptotic Protein Involved in Activation of Caspase-8, Is Essential for 3' End Processing of Histone Pre-mRNAs
Yang XC, Burch BD, Yan Y, Marzluff WF, Dominski Z.
Mol Cell 2009; 36 (2): 267-278
PMID 19854135
 
Expression and Prognostic Significance of the Apoptotic Genes BCL2L13, Livin, and CASP8AP2 in Childhood Acute Lymphoblastic Leukemia
Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu MY, Chang HH, Chang WH, Lin KS, Lin DT.
Leuk Res 2010; 34 (1): 18-23
PMID 20109966
 

Citation

This paper should be referenced as such :
Juárez-Velázquez R, Pérez-Vera P
CASP8AP2 (caspase 8 associated protein 2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CASP8AP2ID926ch6q15.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  del(6q)


External links

Nomenclature
HGNC (Hugo)CASP8AP2   1510
Cards
AtlasCASP8AP2ID926ch6q15
Entrez_Gene (NCBI)CASP8AP2  9994  caspase 8 associated protein 2
AliasesCED-4; FLASH; RIP25
GeneCards (Weizmann)CASP8AP2
Ensembl hg19 (Hinxton)ENSG00000118412 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000118412 [Gene_View]  chr6:89829900-89874436 [Contig_View]  CASP8AP2 [Vega]
ICGC DataPortalENSG00000118412
TCGA cBioPortalCASP8AP2
AceView (NCBI)CASP8AP2
Genatlas (Paris)CASP8AP2
WikiGenes9994
SOURCE (Princeton)CASP8AP2
Genetics Home Reference (NIH)CASP8AP2
Genomic and cartography
GoldenPath hg38 (UCSC)CASP8AP2  -     chr6:89829900-89874436 +  6q15   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CASP8AP2  -     6q15   [Description]    (hg19-Feb_2009)
EnsemblCASP8AP2 - 6q15 [CytoView hg19]  CASP8AP2 - 6q15 [CytoView hg38]
Mapping of homologs : NCBICASP8AP2 [Mapview hg19]  CASP8AP2 [Mapview hg38]
OMIM606880   
Gene and transcription
Genbank (Entrez)AB037736 AF154415 AF164678 AF165161 AJ420582
RefSeq transcript (Entrez)NM_001137667 NM_001137668 NM_012115
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CASP8AP2
Cluster EST : UnigeneHs.558218 [ NCBI ]
CGAP (NCI)Hs.558218
Alternative Splicing GalleryENSG00000118412
Gene ExpressionCASP8AP2 [ NCBI-GEO ]   CASP8AP2 [ EBI - ARRAY_EXPRESS ]   CASP8AP2 [ SEEK ]   CASP8AP2 [ MEM ]
Gene Expression Viewer (FireBrowse)CASP8AP2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9994
GTEX Portal (Tissue expression)CASP8AP2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UKL3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UKL3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UKL3
Splice isoforms : SwissVarQ9UKL3
PhosPhoSitePlusQ9UKL3
Domains : Interpro (EBI)Homeobox-like   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CASP8AP2
DMDM Disease mutations9994
Blocks (Seattle)CASP8AP2
PDB (SRS)2LR8   
PDB (PDBSum)2LR8   
PDB (IMB)2LR8   
PDB (RSDB)2LR8   
Structural Biology KnowledgeBase2LR8   
SCOP (Structural Classification of Proteins)2LR8   
CATH (Classification of proteins structures)2LR8   
SuperfamilyQ9UKL3
Human Protein AtlasENSG00000118412
Peptide AtlasQ9UKL3
HPRD06048
IPIIPI00100798   
Protein Interaction databases
DIP (DOE-UCLA)Q9UKL3
IntAct (EBI)Q9UKL3
FunCoupENSG00000118412
BioGRIDCASP8AP2
STRING (EMBL)CASP8AP2
ZODIACCASP8AP2
Ontologies - Pathways
QuickGOQ9UKL3
Ontology : AmiGODNA binding  transcription corepressor activity  death receptor binding  protein binding  nucleus  cytoplasm  mitochondrion  transcription, DNA-templated  regulation of transcription, DNA-templated  activation of cysteine-type endopeptidase activity involved in apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  cell cycle  signal transduction  extrinsic apoptotic signaling pathway via death domain receptors  extrinsic apoptotic signaling pathway via death domain receptors  cysteine-type endopeptidase activator activity involved in apoptotic process  peptidase activator activity involved in apoptotic process  PML body  SUMO polymer binding  Fas signaling pathway  cellular response to mechanical stimulus  apoptotic signaling pathway  negative regulation of nucleic acid-templated transcription  
Ontology : EGO-EBIDNA binding  transcription corepressor activity  death receptor binding  protein binding  nucleus  cytoplasm  mitochondrion  transcription, DNA-templated  regulation of transcription, DNA-templated  activation of cysteine-type endopeptidase activity involved in apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  cell cycle  signal transduction  extrinsic apoptotic signaling pathway via death domain receptors  extrinsic apoptotic signaling pathway via death domain receptors  cysteine-type endopeptidase activator activity involved in apoptotic process  peptidase activator activity involved in apoptotic process  PML body  SUMO polymer binding  Fas signaling pathway  cellular response to mechanical stimulus  apoptotic signaling pathway  negative regulation of nucleic acid-templated transcription  
NDEx NetworkCASP8AP2
Atlas of Cancer Signalling NetworkCASP8AP2
Wikipedia pathwaysCASP8AP2
Orthology - Evolution
OrthoDB9994
GeneTree (enSembl)ENSG00000118412
Phylogenetic Trees/Animal Genes : TreeFamCASP8AP2
HOVERGENQ9UKL3
HOGENOMQ9UKL3
Homologs : HomoloGeneCASP8AP2
Homology/Alignments : Family Browser (UCSC)CASP8AP2
Gene fusions - Rearrangements
Fusion : COSMICKMT2A [11q23.3]  -  CASP8AP2 [6q15]  [fusion_2058]  
Fusion : TICdbKMT2A [11q23.3]  -  CASP8AP2 [6q15]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCASP8AP2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CASP8AP2
dbVarCASP8AP2
ClinVarCASP8AP2
1000_GenomesCASP8AP2 
Exome Variant ServerCASP8AP2
ExAC (Exome Aggregation Consortium)CASP8AP2 (select the gene name)
Genetic variants : HAPMAP9994
Genomic Variants (DGV)CASP8AP2 [DGVbeta]
DECIPHERCASP8AP2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCASP8AP2 
Mutations
ICGC Data PortalCASP8AP2 
TCGA Data PortalCASP8AP2 
Broad Tumor PortalCASP8AP2
OASIS PortalCASP8AP2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCASP8AP2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCASP8AP2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CASP8AP2
DgiDB (Drug Gene Interaction Database)CASP8AP2
DoCM (Curated mutations)CASP8AP2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CASP8AP2 (select a term)
intoGenCASP8AP2
NCG5 (London)CASP8AP2
Cancer3DCASP8AP2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606880   
Orphanet
MedgenCASP8AP2
Genetic Testing Registry CASP8AP2
NextProtQ9UKL3 [Medical]
TSGene9994
GENETestsCASP8AP2
Target ValidationCASP8AP2
Huge Navigator CASP8AP2 [HugePedia]
snp3D : Map Gene to Disease9994
BioCentury BCIQCASP8AP2
ClinGenCASP8AP2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9994
Chemical/Pharm GKB GenePA26093
Clinical trialCASP8AP2
Miscellaneous
canSAR (ICR)CASP8AP2 (select the gene name)
Probes
Litterature
PubMed58 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCASP8AP2
EVEXCASP8AP2
GoPubMedCASP8AP2
iHOPCASP8AP2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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