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ANP32A (acidic (leucine-rich) nuclear phosphoprotein 32 family, member A)

Written2013-03Richard A Burkhart, Jonathan R Brody
Thomas Jefferson University, Department of Surgery, Philadelphia, PA, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesC15orf1
acidic (leucine-rich) nuclear phosphoprotein 32 family, member A
Alias_symbol (synonym)LANP
PP32
I1PP2A
PHAPI
MAPM
mapmodulin
Other aliasHPPCn
PHAP1
HGNC (Hugo) ANP32A
LocusID (NCBI) 8125
Atlas_Id 647
Location 15q23  [Link to chromosome band 15q23]
Location_base_pair Starts at 68778536 and ends at 68820922 bp from pter ( according to hg19-Feb_2009)  [Mapping ANP32A.png]
Local_order The gene is 73682 bases long and oriented on the minus strand.
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ACTR8 (3p21.1) / ANP32A (15q23)ANP32A (15q23) / ANKRD12 (18p11.22)ANP32A (15q23) / C1orf87 (1p32.1)
ANP32A (15q23) / HES2 (1p36.31)ANP32A (15q23) / MIR548F1 (1q31.1)ANP32A (15q23) / NCL (2q37.1)
ANP32A (15q23) / SURF4 (9q34.2)CEP170B (14q32.33) / ANP32A (15q23)HLA-C (6p21.33) / ANP32A (15q23)
POMT1 (9q34.13) / ANP32A (15q23)

DNA/RNA

 
Description One of 1265 total genes on chromosome 15 according to NCBI Mapviewer. According to Ensembl, a predicted 76 base pair non-coding RNA (ncRNA) for MIR4312-201 is present within the gene sequence on the reverse strand at chromosome 15: 69094189-69094264.
Pseudogene There are multiple genomic regions that have a high degree of similarity with the ANP32A sequence (including anti-sense regions that are most likely abundantly expressed, our data not shown).

Protein

Note N-terminal contains nuclear localizing signals in amphipathic alpha helix with exceptionally acidic c-terminus with aspartic and glutamic acid residues making up about 70% of the domain (Chen et al., 1996). Important features contributing to protein function include the secondary structure of N-terminal leucine-rich repeat domains (Huyton and Wolberger, 2007). Protein is approximately 90% identical to family members pp32r1 and pp32r2, though function is dramatically different and ANP32A tumor suppressor function is dependent upon the region between amino acids 150-174 (Brody et al., 1999). Function is, in part, dependent on phosphorylation status. Casein kinase II has been identified as a mediator of ANP32A phosphorylation in vivo, specifically at serines 158 and 204 (Hong et al., 2004).
Description ANP32A is a 249 amino acid protein (32 kDa) (Li et al., 1996) and represents the first member identified in a family of evolutionarily-conserved phosphoproteins that are involved in an array of gene regulatory and diverse network regulatory functions primarily through protein-protein interactions such as binding to phosphorylated retinoblastoma (Rb) gene product (Adegbola and Pasternack, 2005).
Expression Ubiquitously expressed in human tissues.
Localisation ANP32A is primarily nuclear (Matsuoka et al., 1994; Matilla et al., 1997; Kovacech et al., 2007; Khan et al., 2011) with variable cytoplasmic localization. It participates in nuclear-to-cytoplasmic shuttling as a multi-protein complex with its binding partners (Williams et al., 2010; Santa-Coloma, 2003; Higashino et al., 2005; Mazroui et al., 2008; Pan et al., 2009; Fukumoto et al., 2011). This cytoplasmic translocation is dependent upon the nuclear export factor chromosomal region maintenance protein 1, or CRM1 (Brennan et al., 2000). Of particular importance is the capacity of ANP32A to translocate from the nucleus to the cytoplasm upon cellular stress to disrupt the pro-tumorigenic function of associated protein HuR (Hostetter et al., 2008; Williams et al., 2010). In some cases, ANP32A mediated disruption of HuR function can precipitate caspase-mediated cleavage of HuR (Mazroui et al., 2008). A trimeric form has been found to be located primarily in the cytosol in hamster models (Ulitzur et al., 1997; Itin et al., 1999).
Function ANP32A has a diverse array of functions. The role of ANP32A in oncogenesis, tumor suppression, and cellular differentiation is well established. It has marked tumor suppressor activity and acts in part through the inhibition of ras/Kras-mediated transformation in both in vitro and in vivo studies (Bai et al., 2001). ANP32A participates in transcriptional gene regulation through histone modification as a member of the inhibitor of histone acetyl transferase (INHAT) protein complex (Brody et al., 2004; Santa-Coloma, 2003; Kular et al., 2009; Khan et al., 2011) and through interferon-dependent binding to gene promoters in conjunction with STAT1/STAT2 (Kadota and Nagata, 2011). Participation as a component of the INHAT protein complex is dependent upon its highly-acidic c-terminus interacting with template activating factor-lbeta, or TAF-lbeta (Seo et al., 2002; Lee et al., 2006). It participates in mRNA nuclear-to-cytoplasmic translocation and post-transcriptional gene regulation (Williams et al., 2010; Santa-Coloma, 2003; Fries et al., 2007; Mazroui et al., 2008; Pan et al., 2009) as a key binding partner of HuR and in an importin-alpha dependent manner (Fukumoto et al., 2011). It is a central component of the SET complex at the core of the granzyme A-mediated apoptosis pathway and affects the activation of caspase-9, cytochrome c-induced caspase activation, Apaf-1, and caspase-3 (Hill et al., 2004; Hoffarth et al., 2008; Kim et al., 2008; Li et al., 2012). ANP32A has also been identified as an inhibitor of protein phosphatase 2A, leading to changes in the ERK, MEK, and WNT signaling pathways (Li et al., 1995; Li et al., 1996; Yu et al., 2004; Stelzl et al., 2005; Habrukowich et al., 2010). It is associated with neuronal cell development, neurotoxicity, and microtubule-based cellular vesicular transport through interactions with microtubule associated proteins tau, MAP2, and MAP4 (Ulitzur et al., 1997; Itin et al., 1999; Kovacech et al., 2007; Kular et al., 2009). Also protective of neuronal excitotoxicity and apoptosis through interaction with the retinoblastoma (Rb) gene product (Adegbola and Pasternack, 2005; Khan et al., 2011) and may play a role in the pathogenesis of spinocerebellar ataxia type 1 through an interaction with ataxin-1 in a manner that is enhanced with expanding CAG repeats of the gene (Matilla et al., 1997). As a necessary component of the template activating factor-1/SET oncoprotein complex it is associated with andeno-associated virus replication (Pegoraro et al., 2006). Finally, its association with the alpha chain of HLA class II molecule DR2 is of unclear significance (Vaesen et al., 1994).

Mutations

Note There are currently 607 known single nucleotide polymorphisms (SNP) registered with the NCBI SNP database. Of these, only one is suggested to have clinical relevance thus far.
A single nucleotide polymorphism of the minor allele (rs7164503) appears to be associated with the pathogenesis of osteoarthritis of the hip (Valdes et al., 2009).

Implicated in

Note
  
Entity Prostate adenocarcinoma
Note In 1998, Kadkol et al. used in situ hybridization techniques to compare ANP32A expression in prostatic adenocarcinoma with expression in benign prostatic hyperplasia. While finding only moderate expression in the basal cells, 98% of prostatic adenocarcinomas with high Gleason scores demonstrated elevated levels of ANP32A (Kadkol et al., 1998).
In an effort to clarify the paradoxical finding of elevated levels of a tumor suppressor in transformed pancreatic adenocarcinoma tissue, in 1999 Kadkol and colleagues compared the sequence and function of members of this phosphoprotein family in a series of three patient tumors (compared to adjacent normal prostate tissue). They found ANP32A to be expressed in normal tissue, while closely related gene products pp32r1 and pp32r2 were dominant in the tumor samples (Kadkol et al., 1999).
In 2001, Bai et al. continued the focus from this laboratory on ANP32A with experiments aimed to clarify its tumor suppressor function. They utilized the fibroblast cell line NIH3T3 and showed that anti-sense inhibition of ANP32A lead to reduced serum dependence and loss of contact inhibition. They further demonstrated that ANP32A expression abrogated ras-mediated transformation in both in-vitro and in-vivo models (Bai et al., 2001).
Continuing work from the same laboratory, Brody and colleagues reported in 2004 that reduction of ANP32A expression in a prostate carcinoma cell line induced transformation into a neuronal phenotype associated with growth arrest. This change was associated with reduced SET expression and changes to the acetylation status of histone H4. Further downstream changes in gene expression were noted with effects pathways including: cell cycle, MAP kinases, apoptosis, cytokines, metabolism, PP2A, p53 stabilization, and growth factor receptors (Brody et al., 2004).
Finally, in 2011 Schramedei et al. reported results from a proteomic analysis of changes following miR-21 expression in LNCaP prostate cancer cells. They found ANP32A to be the most strongly down-regulated protein upon miR-21 expression suggesting a regulatory role of miR-21 on ANP32A expression. They also found that enhanced cell viability conferred by miR-21 expression in this prostate cancer cell line was mimicked by direct ANP32A knock-down and mitigated by ANP32A overexpression (Schramedei et al., 2011).
Prognosis Increased ANP32A is associated with higher Gleason score in prostate adenocarcinoma despite equivalent rates of capsular invasion, seminal vesical invasion, and positive surgical margins at the time of resection (Kadkol et al., 1998).
  
  
Entity Pancreatic cancer
Note In 2007, Brody et al. found dramatically decreased levels of ANP32A in poorly differentiated pancreatic tumors and intraductal papillary mucinous neoplasms with moderate dysplasia when compared to healthy pancreatic tissue or well-to-moderately differentiated tumors. Exogenous overexpression of ANP32A in a low-expression pancreatic cancer cell line lead to increased G1 arrest (Brody et al., 2007).
In 2010, Williams and colleagues extended earlier work from the same group by associating low nuclear ANP32A levels with both high grade pancreatic tumors and the presence of lymph node metastasis. Overexpression of ANP32A conferred resistance to therapy with nucleoside analogs gemcitabine and cytarabine while increasing sensitivity to 5-fluorouracil therapy. In accordance with this result, silencing of ANP32A enhanced sensitivity to gemcitabine. A novel interaction with the RNA-binding protein ELAVL1 was described, whereby ANP32A disrupted binding between ELAVL1 and mRNA transcripts such as doxycytidine kinase (dCK) and VEGF. Notably, dCK is the enzyme responsible for metabolism of gemcitabine from its prodrug to active metabolites (Williams et al., 2010).
Prognosis In contrast to findings in the prostate, in pancreatic adenocarcinoma ANP32A is absent or greatly reduced in poorly differentiated tumor when compared to normal pancreatic tissue, early dysplasia, and even well differentiated adenocarcinomas (Brody et al., 2007; Williams et al., 2010).
  
  
Entity Breast cancer
Note In 2001, Kadkol and colleagues investigated the interplay between members of this phosphoprotein family (ANP32A, pp32r1, and pp32r2) in human breast cancer specimens as compared to benign tissue. After showing abundant protein belonging to this family in 100 of 102 specimens examined, they compared relative expression of each family member in five infiltrating breast carcinomas (compared to matching benign breast tissue). Four of five carcinomas continued to express ANP32A (at levels similar to that of the benign samples), however the expression of pp32r1 and pp32r2 was unique to the carcinomas (Kadkol et al., 2001).
In 2006, Schafer et al. utilized a breast cancer model of chemotherapeutic-induced cytochrome-c mediated apoptosis. They found that breast cancer cells were hyper-sensitive to cytochrome-c mediated apoptosis as compared to normal cells. This hypersensitivity resulted in increased caspase 9 activation in a manner that was mediated by increased ANP32A protein (Schafer et al., 2006).
  
  
Entity Non-small cell lung cancer
Note In 2008, Hoffarth and colleagues evaluated the effects of exogenous ANP32A expression on drug resistant non-small cell lung cancer cell (NSCLC) lines. They were able to correlate drug resistance with impaired caspase 9 and caspase 3 activation despite formation of the cytochrome-c induced apoptosome. Expression of ANP32A restored apoptosome activation both in vitro and murine in vivo models. Finally, they correlated improved outcomes following chemotherapy in human NSCLC patients with expression of ANP32A on immunohistochemical staining of tumor samples (Hoffarth et al., 2008).
  
  
Entity Hepatocellular carcinoma
Note In 2012, Li and colleagues surveyed abnormal protein expression in hepatocellular carcinoma utilizing two-dimensional liquid chromatography-tandem mass spectrometry. Elevated expression of ANP32A was validated by western blot analysis and immunohistochemical staining of a tissue microarray comprised of 59 cases (Li et al., 2012).
  
  
Entity Colorectal cancer
Note In 2011, Shi et al. profiled the proteome changes found in laser capture microdissection samples of colorectal cancer. Amongst several novel protein changes found, ANP32A was overexpressed in tumor when compared to normal tissue (Shi et al., 2011).
  
  
Entity Neurotoxicity/neurodegenerative disease
Note An association with Rb-mediated gene repression plays a key role in neuronal protection against excitotoxicity (Khan et al., 2011). May contribute to altered tau protein phosphorylation contributing to the pathophysiology of Alzheimer's disease (Tsujio et al., 2005; Kovacech et al., 2007). In the cerebellum it is primarily located in the nucleus of Purkinje cells where it interacts with ataxin-1, the gene product in spinocerebellar ataxia type 1 (Matilla et al., 1997).
Disease Proposed: Alzheimer's disease, spinocerebellar ataxia type 1.
  
  
Entity Cellular response to immunomodulatory and inflammatory factors
Note Interacts with STAT1/STAT2 and modulates transcriptional complex binding to interferon-stimulated gene promoters (Kadota and Nagata, 2011). Regulates cell signaling in response to inflammatory gene expression through target inhibition of protein phosphatase 2A (Khan et al., 2011). Association with HLA class II molecule DR2 alpha chain has yet to be fully elucidated (Vaesen et al., 1994).
  
  
Entity Embryogenesis
Note In a survey of this family of leucine-rich repeat genes, ANP32A was necessary for murine embryogenesis in a background of ANP32B absence (Reilly et al., 2011).
  
  
Entity Virology
Note ANP32A is required for adeno-associated virus replication in human cell line studies as a member of the template activating factor-I/SET oncoprotein complex (Pegoraro et al., 2006). As part of this process, nuclear-to-cytoplasmic shuttling with HuR takes place in a manner dependent on E4orf6 protein function (Higashino et al., 2005).
  

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Citation

This paper should be referenced as such :
Burkhart, RA ; Brody, JR
ANP32A (acidic (leucine-rich) nuclear phosphoprotein 32 family, member A)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):557-562.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ANP32AID647ch15q23.html

External links

Nomenclature
HGNC (Hugo)ANP32A   13233
Cards
AtlasANP32AID647ch15q23
Entrez_Gene (NCBI)ANP32A  8125  acidic nuclear phosphoprotein 32 family member A
AliasesC15orf1; HPPCn; I1PP2A; LANP; 
MAPM; PHAP1; PHAPI; PP32
GeneCards (Weizmann)ANP32A
Ensembl hg19 (Hinxton)ENSG00000140350 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000140350 [Gene_View]  ENSG00000140350 [Sequence]  chr15:68778536-68820922 [Contig_View]  ANP32A [Vega]
ICGC DataPortalENSG00000140350
TCGA cBioPortalANP32A
AceView (NCBI)ANP32A
Genatlas (Paris)ANP32A
WikiGenes8125
SOURCE (Princeton)ANP32A
Genetics Home Reference (NIH)ANP32A
Genomic and cartography
GoldenPath hg38 (UCSC)ANP32A  -     chr15:68778536-68820922 -  15q23   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ANP32A  -     15q23   [Description]    (hg19-Feb_2009)
GoldenPathANP32A - 15q23 [CytoView hg19]  ANP32A - 15q23 [CytoView hg38]
ImmunoBaseENSG00000140350
Mapping of homologs : NCBIANP32A [Mapview hg19]  ANP32A [Mapview hg38]
OMIM600832   
Gene and transcription
Genbank (Entrez)AF025684 AK127498 AK223280 AK312703 AW383928
RefSeq transcript (Entrez)NM_006305
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ANP32A
Cluster EST : UnigeneHs.458747 [ NCBI ]
CGAP (NCI)Hs.458747
Alternative Splicing GalleryENSG00000140350
Gene ExpressionANP32A [ NCBI-GEO ]   ANP32A [ EBI - ARRAY_EXPRESS ]   ANP32A [ SEEK ]   ANP32A [ MEM ]
Gene Expression Viewer (FireBrowse)ANP32A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8125
GTEX Portal (Tissue expression)ANP32A
Human Protein AtlasENSG00000140350-ANP32A [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP39687   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP39687  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP39687
Splice isoforms : SwissVarP39687
PhosPhoSitePlusP39687
Domaine pattern : Prosite (Expaxy)LRR (PS51450)   
Domains : Interpro (EBI)Leu-rich_rpt    LRR_dom_sf    U2A'_phosphoprotein32A_C   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)LRRcap (SM00446)  
Conserved Domain (NCBI)ANP32A
DMDM Disease mutations8125
Blocks (Seattle)ANP32A
PDB (RSDB)2JE0    2JE1    4XOS   
PDB Europe2JE0    2JE1    4XOS   
PDB (PDBSum)2JE0    2JE1    4XOS   
PDB (IMB)2JE0    2JE1    4XOS   
Structural Biology KnowledgeBase2JE0    2JE1    4XOS   
SCOP (Structural Classification of Proteins)2JE0    2JE1    4XOS   
CATH (Classification of proteins structures)2JE0    2JE1    4XOS   
SuperfamilyP39687
Human Protein Atlas [tissue]ENSG00000140350-ANP32A [tissue]
Peptide AtlasP39687
HPRD09014
Protein Interaction databases
DIP (DOE-UCLA)P39687
IntAct (EBI)P39687
FunCoupENSG00000140350
BioGRIDANP32A
STRING (EMBL)ANP32A
ZODIACANP32A
Ontologies - Pathways
QuickGOP39687
Ontology : AmiGORNA binding  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  endoplasmic reticulum  nucleocytoplasmic transport  nucleocytoplasmic transport  nucleocytoplasmic transport  intracellular signal transduction  histone binding  regulation of mRNA stability  perinuclear region of cytoplasm  perinuclear region of cytoplasm  
Ontology : EGO-EBIRNA binding  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  endoplasmic reticulum  nucleocytoplasmic transport  nucleocytoplasmic transport  nucleocytoplasmic transport  intracellular signal transduction  histone binding  regulation of mRNA stability  perinuclear region of cytoplasm  perinuclear region of cytoplasm  
REACTOMEP39687 [protein]
REACTOME PathwaysR-HSA-450520 [pathway]   
NDEx NetworkANP32A
Atlas of Cancer Signalling NetworkANP32A
Wikipedia pathwaysANP32A
Orthology - Evolution
OrthoDB8125
GeneTree (enSembl)ENSG00000140350
Phylogenetic Trees/Animal Genes : TreeFamANP32A
HOGENOMP39687
Homologs : HomoloGeneANP32A
Homology/Alignments : Family Browser (UCSC)ANP32A
Gene fusions - Rearrangements
Fusion Cancer (Beijing)HLA-C [6p21.33]  -  ANP32A [15q23]  [FUSC000443]
Fusion Cancer (Beijing)JA040725 [ANP32A]  -  15q23 [FUSC000743]  [FUSC000743]  [FUSC000743]
Fusion : FusionGDB1951    1952    1953    1954    1955    28025   
Fusion : Fusion_HubABR--ANP32A    ACTR8--ANP32A    ANP32A--ANKRD12    ANP32A--BASP1    ANP32A--C1ORF87    ANP32A--COMMD4    ANP32A--COPA    ANP32A--HES2    ANP32A--MIR548F1    ANP32A--NCL    ANP32A--PDXK    ANP32A--PTTG1IP    ANP32A--RHOA    ANP32A--ST20    ANP32A--SURF4   
ARIH1--ANP32A    CALM2--ANP32A    CD82--ANP32A    CLIC4--ANP32A    CORO2B--ANP32A    FOXN3--ANP32A    HLA-C--ANP32A    JA040725--ANP32A    KDM6B--ANP32A    KRCC1--ANP32A    MARCKS--ANP32A    MYBL2--ANP32A    NDUFS2--ANP32A    PHACTR3--ANP32A    POMT1--ANP32A   
SEMA4B--ANP32A    SMC6--ANP32A   
Fusion : QuiverANP32A
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerANP32A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ANP32A
dbVarANP32A
ClinVarANP32A
1000_GenomesANP32A 
Exome Variant ServerANP32A
ExAC (Exome Aggregation Consortium)ENSG00000140350
GNOMAD BrowserENSG00000140350
Varsome BrowserANP32A
Genetic variants : HAPMAP8125
Genomic Variants (DGV)ANP32A [DGVbeta]
DECIPHERANP32A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisANP32A 
Mutations
ICGC Data PortalANP32A 
TCGA Data PortalANP32A 
Broad Tumor PortalANP32A
OASIS PortalANP32A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICANP32A  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DANP32A
Mutations and Diseases : HGMDANP32A
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 ANP32A
DgiDB (Drug Gene Interaction Database)ANP32A
DoCM (Curated mutations)ANP32A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ANP32A (select a term)
intoGenANP32A
NCG5 (London)ANP32A
Cancer3DANP32A(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600832   
Orphanet
DisGeNETANP32A
MedgenANP32A
Genetic Testing Registry ANP32A
NextProtP39687 [Medical]
TSGene8125
GENETestsANP32A
Target ValidationANP32A
Huge Navigator ANP32A [HugePedia]
snp3D : Map Gene to Disease8125
BioCentury BCIQANP32A
ClinGenANP32A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8125
Chemical/Pharm GKB GenePA24811
Clinical trialANP32A
Miscellaneous
canSAR (ICR)ANP32A (select the gene name)
DataMed IndexANP32A
Probes
Litterature
PubMed88 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineANP32A
EVEXANP32A
GoPubMedANP32A
iHOPANP32A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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