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

2013-03-01   Richard A Burkhart , Jonathan R Brody 

Thomas Jefferson University, Department of Surgery, Philadelphia, PA, USA




Atlas Image


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.


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).



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).


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).


Ubiquitously expressed in human tissues.


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).


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).



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

Entity name
Prostate adenocarcinoma
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).
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 name
Pancreatic cancer
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).
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 name
Breast cancer
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 name
Non-small cell lung cancer
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 name
Hepatocellular carcinoma
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 name
Colorectal cancer
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 name
Neurotoxicity/neurodegenerative disease
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 Alzheimers 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).
Proposed: Alzheimers disease, spinocerebellar ataxia type 1.
Entity name
Cellular response to immunomodulatory and inflammatory factors
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 name
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 name
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).


Pubmed IDLast YearTitleAuthors
157162732005Phosphorylated retinoblastoma protein complexes with pp32 and inhibits pp32-mediated apoptosis.Adegbola O et al
113601992001Tumor suppression and potentiation by manipulation of pp32 expression.Bai J et al
110180492000Protein ligands to HuR modulate its interaction with target mRNAs in vivo.Brennan CM et al
146953402004pp32 reduction induces differentiation of TSU-Pr1 cells.Brody JR et al
179066142007Reduction of pp32 expression in poorly differentiated pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms with moderate dysplasia.Brody JR et al
89701641996Structure of pp32, an acidic nuclear protein which inhibits oncogene-induced formation of transformed foci.Chen TH et al
85300981995Localization of the gene encoding the putative human HLA class II associated protein (PHAPI) to chromosome 15q22.3-q23 by fluorescence in situ hybridization.Fink TM et al
171787122007Analysis of nucleocytoplasmic trafficking of the HuR ligand APRIL and its influence on CD83 expression.Fries B et al
213076072011Proteomic analysis of importin α-interacting proteins in adult mouse brain.Fukumoto M et al
205587412010Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells.Habrukowich C et al
159830582005Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism.Higashino F et al
151033272004Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes.Hill MM et al
179628132008pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer.Hoffarth S et al
152877432004The identification of phosphorylation sites of pp32 and biochemical purification of a cellular pp32-kinase.Hong R et al
187691292008Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor positive breast cancer cells.Hostetter C et al
175677412007The crystal structure of the tumor suppressor protein pp32 (Anp32a): structural insights into Anp32 family of proteins.Huyton T et al
103977581999Mapmodulin, cytoplasmic dynein, and microtubules enhance the transport of mannose 6-phosphate receptors from endosomes to the trans-golgi network.Itin C et al
100863811999Modulation of oncogenic potential by alternative gene use in human prostate cancer.Kadkol SS et al
116783102001Expression of pp32 gene family members in breast cancer.Kadkol SS et al
213250292011pp32, an INHAT component, is a transcription machinery recruiter for maximal induction of IFN-stimulated genes.Kadota S et al
206174642011CXCL12-mediated regulation of ANP32A/Lanp, a component of the inhibitor of histone acetyl transferase (INHAT) complex, in cortical neurons.Khan MZ et al
184399022008PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1.Kim HE et al
172669542007A novel monoclonal antibody DC63 reveals that inhibitor 1 of protein phosphatase 2A is preferentially nuclearly localised in human brain.Kovacech B et al
191365652009Neuronal differentiation is regulated by leucine-rich acidic nuclear protein (LANP), a member of the inhibitor of histone acetyltransferase complex.Kular RK et al
171429702006Highly acidic C-terminal domain of pp32 is required for the interaction with histone chaperone, TAF-Ibeta.Lee IS et al
220822272012Quantitative proteomics reveal up-regulated protein expression of the SET complex associated with hepatocellular carcinoma.Li C et al
75314971995Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney.Li M et al
86795241996Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A.Li M et al
93531211997The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1.Matilla A et al
79378701994A nuclear factor containing the leucine-rich repeats expressed in murine cerebellar neurons.Matsuoka K et al
181803672008Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis.Mazroui R et al
191219992009PHAPI/pp32 suppresses tumorigenesis by stimulating apoptosis.Pan W et al
168092912006Regulation of adeno-associated virus DNA replication by the cellular TAF-I/set complex.Pegoraro G et al
216367892011Acidic nuclear phosphoprotein 32kDa (ANP32)B-deficient mouse reveals a hierarchy of ANP32 importance in mammalian development.Reilly PT et al
149646902003Anp32e (Cpd1) and related protein phosphatase 2 inhibitors.Santa-Coloma TA et al
164890232006Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells.Schafer ZT et al
213179272011MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4.Schramedei K et al
118305912002Regulation of histone acetylation and transcription by nuclear protein pp32, a subunit of the INHAT complex.Seo SB et al
218436672011Proteomic analysis of advanced colorectal cancer by laser capture microdissection and two-dimensional difference gel electrophoresis.Shi H et al
161690702005A human protein-protein interaction network: a resource for annotating the proteome.Stelzl U et al
156423452005Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau.Tsujio I et al
93745541997Biochemical characterization of mapmodulin, a protein that binds microtubule-associated proteins.Ulitzur N et al
81928561994Purification and characterization of two putative HLA class II associated proteins: PHAPI and PHAPII.Vaesen M et al
195654872009Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women.Valdes AM et al
211520642010pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.Williams TK et al
152472762004Protein phosphatase 2A, a negative regulator of the ERK signaling pathway, is activated by tyrosine phosphorylation of putative HLA class II-associated protein I (PHAPI)/pp32 in response to the antiproliferative lectin, jacalin.Yu LG et al

Other Information

Locus ID:

NCBI: 8125
MIM: 600832
HGNC: 13233
Ensembl: ENSG00000140350


dbSNP: 8125
ClinVar: 8125
TCGA: ENSG00000140350


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
HuR (ELAVL1) binds and stabilizes mRNAREACTOMER-HSA-450520

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
161690702005A human protein-protein interaction network: a resource for annotating the proteome.843
125222432003Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway.89
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
267385962016Species difference in ANP32A underlies influenza A virus polymerase host restriction.69
118305912002Regulation of histone acetylation and transcription by nuclear protein pp32, a subunit of the INHAT complex.46
213179272011MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4.46
151365632004A signaling role of histone-binding proteins and INHAT subunits pp32 and Set/TAF-Ibeta in integrating chromatin hypoacetylation and transcriptional repression.44
184399022008PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1.44
128079132003Mapmodulin/leucine-rich acidic nuclear protein binds the light chain of microtubule-associated protein 1B and modulates neuritogenesis.31
152472762004Protein phosphatase 2A, a negative regulator of the ERK signaling pathway, is activated by tyrosine phosphorylation of putative HLA class II-associated protein I (PHAPI)/pp32 in response to the antiproliferative lectin, jacalin.25


Richard A Burkhart ; Jonathan R Brody

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

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

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