CASP8AP2 (caspase 8 associated protein 2)

2015-03-01   Rocío Juárez-Velázquez , Patricia Pérez-Vera 

Laboratorio de Cultivo de Tejidos, Departamento de Genética Humana, Instituto Nacional de Pediatria, Mexico, Mexico; pperezvera@yahoo.com

Identity

HGNC
LOCATION
6q15 ; CASP8AP2 gene is located on the long arm of chromosome 6 NC_000006.12, in opposite orientation
LOCUSID
ALIAS
CED-4,FLASH,RIP25
FUSION GENES

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.

DNA/RNA

Atlas Image
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.

Proteins

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

Entity name
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 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 name
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 name
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 name
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

Pubmed IDLast YearTitleAuthors
196159802009SUMO modification regulates the transcriptional activity of FLASH.Alm-Kristiansen AH et al
170031252006FLASH is required for histone transcription and S-phase progression.Barcaroli D et al
255305662015Low 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 et al
217253622012FLASH is essential during early embryogenesis and cooperates with p73 to regulate histone gene transcription.De Cola A et al
174567222007A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia.Flotho C et al
102352591999The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis.Imai Y et al
216968252012CASP8AP2 is a promising prognostic indicator in pediatric acute lymphoblastic leukemia.Jiao Y et al
243975962014Significance of CASP8AP2 and H2AFZ expression in survival and risk of relapse in children with acute lymphoblastic leukemia.Juárez-Velázquez R et al
124777262003Tumor 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 et al
195462342009Interaction of FLASH with arsenite resistance protein 2 is involved in cell cycle progression at S phase.Kiriyama M et al
225954582012Targeted Casp8AP2 methylation increases drug resistance in mesenchymal stem cells and cancer cells.Lee KD et al
239539142013Hypermethylation of two CpG sites upstream of CASP8AP2 promoter influences gene expression and treatment outcome in childhood acute lymphoblastic leukemia.Li ZG et al
198372772009CASP8AP2 is a novel partner gene of MLL rearrangement with t(6;11)(q15;q23) in acute myeloid leukemia.Park TS et al
194069882009High-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 et al
250424052015Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis.Scholtysik R et al
198541352009FLASH, a proapoptotic protein involved in activation of caspase-8, is essential for 3' end processing of histone pre-mRNAs.Yang XC et al
201099662010Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia.Yang YL et al

Other Information

Locus ID:

NCBI: 9994
MIM: 606880
HGNC: 1510
Ensembl: ENSG00000118412

Variants:

dbSNP: 9994
ClinVar: 9994
TCGA: ENSG00000118412
COSMIC: CASP8AP2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000118412ENST00000419040A0A096LP21
ENSG00000118412ENST00000551025A0A087WTW5
ENSG00000118412ENST00000552401A0A096LP21

Expression (GTEx)

0
5
10
15

References

Pubmed IDYearTitleCitations
198541352009FLASH, a proapoptotic protein involved in activation of caspase-8, is essential for 3' end processing of histone pre-mRNAs.63
170031252006FLASH is required for histone transcription and S-phase progression.56
186771002008FLASH and NPAT positive but not Coilin positive Cajal Bodies correlate with cell ploidy.42
195462342009Interaction of FLASH with arsenite resistance protein 2 is involved in cell cycle progression at S phase.34
230710922013A complex containing the CPSF73 endonuclease and other polyadenylation factors associates with U7 snRNP and is recruited to histone pre-mRNA for 3'-end processing.33
194069882009High-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.32
166277602006Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2.31
172454292007FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies.29
170031262006FLASH is an essential component of Cajal bodies.28
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27

Citation

Rocío Juárez-Velázquez ; Patricia Pérez-Vera

CASP8AP2 (caspase 8 associated protein 2)

Atlas Genet Cytogenet Oncol Haematol. 2015-03-01

Online version: http://atlasgeneticsoncology.org/gene/926/casp8ap2