Gene Summary

Gene:ANP32A; acidic nuclear phosphoprotein 32 family member A
Aliases: LANP, MAPM, PP32, HPPCn, PHAP1, PHAPI, I1PP2A, C15orf1
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:acidic leucine-rich nuclear phosphoprotein 32 family member A
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (13)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Nuclear Proteins
  • Protein Binding
  • Protein Transport
  • Molecular Sequence Data
  • Vimentin
  • Phosphoprotein Phosphatases
  • Tumor Stem Cell Assay
  • Histone Chaperones
  • Nuclear Localization Signals
  • Caspases
  • RNA Stability
  • Chromosome 15
  • p38 Mitogen-Activated Protein Kinases
  • Transfection
  • Lymphatic Metastasis
  • Base Sequence
  • Messenger RNA
  • Cell Proliferation
  • Prostate Cancer
  • Cell Survival
  • Phosphorylation
  • Neoplastic Cell Transformation
  • RNA-Binding Proteins
  • Adenoviridae Infections
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • ELAVL1
  • Regulatory Elements, Transcriptional
  • Intracellular Signaling Peptides and Proteins
  • Protein Structure, Tertiary
  • Two-Dimensional Difference Gel Electrophoresis
  • Cloning, Molecular
  • Histones
  • Acute Myeloid Leukaemia
  • Brain Tumours
  • Apoptosis
  • Cell Cycle
  • Cultured Cells
  • Transcription Factors
  • Immunohistochemistry
  • MicroRNAs
  • Pancreatic Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ANP32A (cancer-related)

Yang X, Lu B, Sun X, et al.
ANP32A regulates histone H3 acetylation and promotes leukemogenesis.
Leukemia. 2018; 32(7):1587-1597 [PubMed] Related Publications
Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression. Notably, significant histone H3 acetylation enrichment was associated with mRNA changes in lipid-related genes, including APOC1, PCSK9, P2RX1, and LPPR3. Indeed, over-expression of APOC1 partially compensated the proliferation-defect phenotype in ANP32A deficient AML cells while APOC1 knockdown alone mimicked the effect of ANP32A deficiency. Collectively, our data indicate that ANP32A is a novel regulator of histone H3 acetylation and promotes leukemogenesis.

Jehung JP, Kitamura T, Yanagawa-Matsuda A, et al.
Adenovirus infection induces HuR relocalization to facilitate virus replication.
Biochem Biophys Res Commun. 2018; 495(2):1795-1800 [PubMed] Related Publications
HuR is an RNA-binding protein of the embryonic lethal abnormal vision (ELAV) family, which binds to the AU-rich element (ARE) in the 3'-untranslated region (UTR) of certain mRNAs and is involved in the nucleo-cytoplasmic export and stabilization of ARE-mRNAs. The cytoplasmic relocalization of ARE-mRNAs with several proteins such as HuR and pp32 increases in cells transformed by the adenovirus oncogene product E4orf6. Additionally, these ARE-mRNAs were stabilized and acquired the potential to transform cells. Although, the relocalization of HuR and the stabilization of ARE-mRNAs are crucial for cell transformation, evidence regarding the relationship of HuR and ARE-mRNAs with adenovirus replication is lacking. In this report, we demonstrate that adenovirus infection induces the relocation of HuR to the cytoplasm of host cells. Analysis using the luciferase-ARE fusion gene and the tetracycline (tet)-off system revealed that the process of stabilizing ARE-mRNAs is activated in adenovirus-infected cells. Heat shock treatment or knockdown-mediated depletion of HuR reduced adenovirus production. Furthermore, expression of ARE-including viral IVa2 mRNA, decreased in HuR-depleted infected cells. These results indicate that HuR plays an important role in adenovirus replication, at least in part, by up-regulating IVa2 mRNA expression and that ARE-mRNA stabilization is required for both transformation and virus replication.

Yan W, Bai Z, Wang J, et al.
ANP32A modulates cell growth by regulating p38 and Akt activity in colorectal cancer.
Oncol Rep. 2017; 38(3):1605-1612 [PubMed] Related Publications
Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) possesses multiple biochemical activities, has been found to be decreased or absent in malignant tumors. However, new findings have shown that it is expressed in greater amounts in advanced cancers than in early-stage tumors. The role and clinical significance of ANP32A in colorectal cancer (CRC) is still unknown. In the present study, the expression of ANP32A was assessed in 68 CRC patients by IHC, and then the correlation of its expression with clinicopathological factors was investigated using the Allred, Klein and immune response scoring system analysis. Western blot and real-time PCR analyses were used to assess ANP32A expression and the activity of Akt and p38 in cancer and normal tissues. These data indicated a significant association between ANP32A expression and the activity of Akt and p38, besides the tumor differentiation status in CRC patients. IHC and western blotting data revealed that ANP32A was overexpressed in CRC patients, and ANP32A levels were higher in poorly differentiated tumors. Protein and mRNA analysis revealed that with a high expression of ANP32A, the activation of Akt was enhanced, while the p-38 phosphorylation level was decreased in CRC tissues. MTT assay and functional studies revealed that knockdown of ANP32A inhibited cell growth and induced p38 phosphorylation and Akt dephosphorylation. The present study indicated that ANP32A promoted CRC proliferation by inhibition of p38 and activation of Akt signaling pathways and suggested that ANP32A may play a potential role in CRC diagnosis and therapy.

Uzozie AC, Selevsek N, Wahlander A, et al.
Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis.
Mol Cell Proteomics. 2017; 16(3):407-427 [PubMed] Free Access to Full Article Related Publications
Targeted proteomic methods can accelerate the verification of multiple tumor marker candidates in large series of patient samples. We utilized the targeted approach known as selected/multiple reaction monitoring (S/MRM) to verify potential protein markers of colorectal adenoma identified by our group in previous transcriptomic and quantitative shotgun proteomic studies of a large cohort of precancerous colorectal lesions. We developed SRM assays to reproducibly detect and quantify 25 (62.5%) of the 40 selected proteins in an independent series of precancerous and cancerous tissue samples (19 adenoma/normal mucosa pairs; 17 adenocarcinoma/normal mucosa pairs). Twenty-three proteins were significantly up-regulated (

Vesely DL
Heart Peptide Hormones: Adjunct and Primary Treatments of Cancer.
Anticancer Res. 2016; 36(11):5693-5700 [PubMed] Related Publications
Four heart hormones, namely atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide reduce up to 97% of cancer cells in vitro. These four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast carcinomas and up to 86% of human small-cell lung carcinomas growing in athymic mice. ANP given intravenously for 3 hours after 'curative' lung surgery as an adjunct to surgery results in a 2-year relapse-free survival of 91% compared to 75% for those treated with surgery alone. The anticancer mechanisms of action of these peptides involve binding to receptors on the cancer cells, followed by 95% inhibition of the conversion of inactive to active rat sarcoma-bound guanosine triphosphate (RAS)-mitogen-activated protein kinase (MAPK) kinases 1/2 (MEK 1/2) (98% inhibition)-extracellular signal-related kinases 1/2 (ERK1/2) (96% inhibition) cascade in cancer cells. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGF2 receptor (up to 89%). They also inhibit MAPK9, i.e. c-JUN-N-terminal kinase 2. One of the downstream targets of VEGF is β-catenin, which these peptides inhibit by up to 88%. These four peptide hormones inhibit the Wingless-related integration site (WNT) pathway 68% and WNT secreted-Frizzled protein is reduced by up to 84%. Signal transducer and activator of transcription 3 (STAT3), a final 'switch' that activates gene expression that leads to malignancy, is specifically reduced up to 88% by these peptides but they do not affect STAT1. There is crosstalk between the RAS-MEK 1/2-ERK 1/2 kinase cascade, VEGF, β-catenin, JNK, WNT, and STAT pathways and each of these pathways and their crosstalk is inhibited by these peptide hormones. They enter the nucleus of cancer cells where they inhibit the proto-oncogenes c-FOS (by up to 82%) and c-JUN (by up to 61%).
CONCLUSION: These multiple kinase inhibitors have both adjunct and primary anticancer effects.

Schmidt LH, Görlich D, Spieker T, et al.
Prognostic impact of Bcl-2 depends on tumor histology and expression of MALAT-1 lncRNA in non-small-cell lung cancer.
J Thorac Oncol. 2014; 9(9):1294-304 [PubMed] Related Publications
INTRODUCTION: Apoptosis is a crucial pathway in tumor growth and metastatic development. Apoptotic proteins regulate the underlying molecular cascades and are thought to modulate the tumor response to chemotherapy and radiation. However, the prognostic value of the expression of apoptosis regulators in localized non-small-cell lung cancer (NSCLC) is still unclear.
METHODS: We investigated the protein expression of apoptosis regulators Bcl-2, Bcl-xl, Mcl-1, and pp32/PHAPI, and the expression of the lncRNA MALAT-1 in tumor samples from 383 NSCLC patients (median age: 65.6 years; 77.5% male; paraffin-embedded tissue microarrays). For statistical analysis correlation tests, Log rank tests and Cox proportional hazard models were applied.
RESULTS: Tumor histology was significantly associated with the expression of Bcl-2, Bcl-xl and Mcl-1 (all p < 0.001). Among the tested apoptotic markers only Bcl-2 demonstrated prognostic impact (hazard ratio = 0.64, p = 0.012). For NSCLC patients with non-adenocarcinoma histology, Bcl-2 expression was associated with increased overall survival (p = 0.036). Besides tumor histology, prognostic impact of Bcl-2 was also found to depend on MALAT-1 lncRNA expression. Gene expression analysis of A549 adenocarcinoma cells with differential MALAT-1 lncRNA expression demonstrated an influence on the expression of Bcl-2 and its interacting proteins.
CONCLUSIONS: Bcl-2 expression was specifically associated with superior prognosis in localized NSCLC. An interaction of Bcl-2 with MALAT-1 lncRNA expression was revealed, which merits further investigation for risk prediction in resectable NSCLC patients.

Vesely DL
Family of peptides synthesized in the human body have anticancer effects.
Anticancer Res. 2014; 34(4):1459-66 [PubMed] Related Publications
UNLABELLED: Four peptides synthesized in the heart, namely atrial natriuretic peptide (ANP), vessel dilator, kaliuretic peptide and long-acting natriuretic peptide (LANP), reduce cancer cells in vitro by up to 97%. These four cardiac hormones, in vivo, eliminate up to 86% of human small-cell lung carcinomas, two-thirds of human breast carcinomas, and up to 80% of human pancreatic adenocarcinomas growing in athymic mice. Their anticancer mechanisms of action, after binding to specific receptors on cancer cells, include targeting the Rat sarcoma-bound guanosine triphosphate (RAS) (95% inhibition)-mitogen activated protein kinase kinase 1/2 (MEK-1/2) (98% inhibition)-extracellular signal-related kinases 1/2 (ERK-1/2) (96% inhibition) cascade in cancer cells. They also inhibit MAPK9, i.e. c-JUN-N-terminal kinase 2. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGFR2 receptor (up to 89%). One of their downstream targets of VEGF is β-Catenin, which they reduce up to 88%. The Wingless-related integration site (WNT) pathway is inhibited by up to 68% and WNT secreted-Frizzled related protein-3 was reduced by up to 84% by the four peptide hormones. A serine/threonine-protein kinase, AKT, derived from "AK" mouse strain with thymomas (T), is reduced by up to 64% by the peptide hormones. Signal transducer and activator of transcription 3 (STAT3), a final "switch" that activates gene expression patterns that lead to malignancy, is decreased by up to 88% by these peptide hormones; STAT3 is specifically reduced as they do not affect STAT1. There is cross-talk between the RAS-MEK-1/2-ERK-1/2 kinase cascade, VEGF, β-catenin, WNT, JNK and STAT pathways and each of these pathways is inhibited by the cardiac peptides. These peptides have been demonstrated to enter the nucleus of cancer cells where they inhibit the proto-oncogenes c-FOS (up to 82%) and c-JUN (up to 61%).
CONCLUSION: The cardiac peptides inhibit multiple targets and cross-talk between the targets within cancer cells.

Manimala NJ, Frost CD, Lane ML, et al.
Cardiac hormones target nuclear oncogenes c-Fos and c-Jun in carcinoma cells.
Eur J Clin Invest. 2013; 43(11):1156-62 [PubMed] Related Publications
BACKGROUND: c-Fos is a cellular proto-oncogene which dimerizes with c-Jun proto-oncogene to form AP-1 transcription factor, which upregulates transcription of genes involved in proliferation and cancer formation. Four cardiac hormones, that is, long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide (KP) and atrial natriuretic peptide (ANP) with anticancer effects in vivo are potent inhibitors of the Ras-MEK 1/2-ERK 1/2 kinase cascade and signal transducer and activator of transcription-3 (STAT-3) that activate c-Fos and c-Jun. These four cardiac hormones were investigated for their effects on proto-oncogenes c-Fos and c-Jun within the nucleus of cancer cells.
MATERIALS AND METHODS: Four cardiac hormones were evaluated for their ability to decrease proto-oncogenes c-Fos and c-Jun, measured by ELISA in extracted nuclei of three human cancer cell lines.
RESULTS: Vessel dilator, LANP, KP and ANP over a concentration range of 100 pM-10 μM, maximally decreased c-Fos by 61%, 60%, 61% and 59% in human hepatocellular cancer cells, by 82%, 74%, 78% and 74% in small-cell lung cancer cells, and by 82%, 73%, 78% and 74% in human renal adenocarcinoma cells. c-Jun was maximally reduced by vessel dilator, LANP, KP and ANP by 43%, 31%, 61% and 35% in hepatocellular cancer cells, by 65%, 49%, 59% and 40% in small-cell lung cancer cells, and by 47%, 43%, 57% and 49% in renal cancer cells.
CONCLUSION: Four cardiac hormones are potent inhibitors of c-Fos and c-Jun proto-oncogenes within the nucleus of cancer cells.

Lane ML, Frost CD, Nguyen JP, et al.
Potent selective inhibition of STAT 3 versus STAT 1 by cardiac hormones.
Mol Cell Biochem. 2012; 371(1-2):209-15 [PubMed] Related Publications
Signal transducers and activators of transcription (STATs) are the final "switches" that activate gene expression patterns that lead to human malignancy. Extracellular signal-regulated kinases (ERK 1/2) activate STAT 3; four cardiovascular hormones inhibit ERK 1/2 kinases, leading to the hypothesis that they may also inhibit STATs. These four cardiac hormones, i.e., vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP), eliminate human cancers growing in mice. These four cardiac hormones' effects on STATs 1 and 3 were examined in human small-cell lung cancer and human pancreatic adenocarcinoma cells. Vessel dilator, LANP, kaliuretic peptide, and ANP maximally decreased STAT 3 by 88, 54, 55, and 65 %, respectively, at their 1 μM concentrations in human small-cell lung cancer cells and STAT 3 by 66, 57, 70, and 77 % in human pancreatic adenocarcinoma cells, respectively. The cardiac hormones (except LANP) also significantly decreased STAT 3 measured by Western blots. These cardiac hormones did not decrease STAT 1 in either human small-cell lung cancer or pancreatic adenocarcinoma cells. We conclude that these four cardiac hormones are significant inhibitors of STAT 3, but not STAT 1, in human small-cell lung cancer and pancreatic adenocarcinoma cells, which suggests a specificity for these hormones' anticancer mechanism(s) of action enzymology in human cancer cells.

Reilly PT, Afzal S, Gorrini C, et al.
Acidic nuclear phosphoprotein 32kDa (ANP32)B-deficient mouse reveals a hierarchy of ANP32 importance in mammalian development.
Proc Natl Acad Sci U S A. 2011; 108(25):10243-8 [PubMed] Free Access to Full Article Related Publications
The highly conserved ANP32 proteins are proposed to function in a broad array of physiological activities through molecular mechanisms as diverse as phosphatase inhibition, chromatin regulation, caspase activation, and intracellular transport. On the basis of previous analyses of mice bearing targeted mutations of Anp32a or Anp32e, there has been speculation that all ANP32 proteins play redundant roles and are dispensable for normal development. However, more recent work has suggested that ANP32B may in fact have functions that are not shared by other ANP32 family members. Here we report that ANP32B expression is associated with a poor prognosis in human breast cancer, consistent with the increased levels of Anp32b mRNA present in proliferating wild-type (WT) murine embryonic fibroblasts and stimulated WT B and T lymphocytes. Moreover, we show that, contrary to previous assumptions, Anp32b is very important for murine embryogenesis. In a mixed genetic background, ANP32B-deficient mice displayed a partially penetrant perinatal lethality that became fully penetrant in a pure C57BL/6 background. Surviving ANP32B-deficient mice showed reduced viability due to variable defects in various organ systems. Study of compound mutants lacking ANP32A, ANP32B, and/or ANP32E revealed previously hidden roles for ANP32A in mouse development that became apparent only in the complete absence of ANP32B. Our data demonstrate a hierarchy of importance for the mammalian Anp32 genes, with Anp32b being the most critical for normal development.

Kuroshima T, Aoyagi M, Yasuda M, et al.
Viral-mediated stabilization of AU-rich element containing mRNA contributes to cell transformation.
Oncogene. 2011; 30(26):2912-20 [PubMed] Related Publications
E4orf6 is one of the oncogene products of adenovirus, and it also has an important role for transportation of cellular and viral messenger RNA (mRNA) during the late phase of virus infection. We previously revealed that E4orf6 controls the fate of AU-rich element (ARE) containing mRNA by perturbing the chromosome maintenance region 1-dependent export mechanism. Here, we show that E4orf6 stabilizes ARE-mRNA through the region required for its oncogenic activity and ubiquitin E3 ligase assembly. Cells that failed to stabilize ARE-mRNA after HuR knockdown were unable to produce colonies in soft agar, even when E4orf6 was expressed. Furthermore, the stabilized ARE-mRNA induced the transformation of rodent immortalized cells. These findings indicate that stabilized ARE-mRNA is necessary, if not all, for the oncogenic activity of E4orf6 and has the potential to transform cells, at least under a certain condition.

Schramedei K, Mörbt N, Pfeifer G, et al.
MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4.
Oncogene. 2011; 30(26):2975-85 [PubMed] Free Access to Full Article Related Publications
MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR-21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21.

Zhu BD, Li XL, Liu Y, et al.
Involvement of hepatopoietin Cn in the development of human hepatocellular carcinoma.
Clin Exp Metastasis. 2010; 27(8):571-80 [PubMed] Related Publications
Hepatopoietin Cn (HPPCn) is a novel nuclear protein with the ability to promote liver regeneration. In the present study, we investigated the expression profile of HPPCn and its functional activity in human hepatocellular carcinoma (HCC) cell line and tissue samples. HPPCn expression was detected in HCC cell lines and 54 paired HCC carcinomas by immunochemical staining and Western blotting. The functional activity of HPPCn in cell lines was evaluated by MTT and colony formation assays and with nude mouse model. The correlation of HPPCn expression with clinicopathological characteristics of 54 HCC patients was also analyzed. Our results showed that HPPCn protein was prominently located within the nuclei of hepatocytes and the expression level was evidently increased in HepG2 and Bel7402 cell lines compared with L02 normal hepatocytes. HPPCn silencing by small interfering RNA greatly suppressed HepG2 cell proliferation and colony formation capacity and the inhibitory effect was also observed in a Balb/c-null mouse model. The silencing HPPCn expression effectively enhanced the apoptosis of HepG2 cells. In addition, HPPCn expression was detected in 48 of 54 (89%) human HCC tissues in sharp contrast with the corresponding non-tumor liver tissues. HPPCn protein was mainly accumulated in the tumor nucleus. The elevated expression of HPPCn protein in tumors was significantly associated with poor tumor cellular differentiation and present of vascular invasion. Patients with higher HPPCn expression in tumors had significantly shorter overall survival (OS) of both all of patients and the patients at the early stage. On multivariate Cox analysis, elevated expression of HPPCn in tumors was found to be an independent prognostic factor for OS. Therefore, these data suggest that HPPCn expression might be involved in the development of HCC and could be served as a promising biomarker.

Lenz A, Sun Y, Eichelbaum EJ, et al.
Cardiac hormones eliminate some human squamous lung carcinomas in athymic mice.
Eur J Clin Invest. 2010; 40(3):242-9 [PubMed] Related Publications
BACKGROUND: Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, have anticancer effects in vitro.
MATERIALS AND METHODS: These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 0.3 nM kg(-1) body weight in athymic mice bearing human squamous cell carcinomas.
RESULTS: Vessel dilator, atrial natriuretic peptide and kaliuretic peptide each eliminated one in six (17%) of the human squamous cell lung carcinomas. Long-acting natriuretic peptide, although it did not eliminate any of the human squamous cell lung carcinomas did decrease the volume of one carcinoma to only 2% (P < 0.0001) of the untreated carcinomas. The squamous cell lung carcinomas that were not eliminated, with the exception of the one LANP-treated tumour that decreased to only 2% of the volume of the untreated cancers, grew rapidly but their growth velocity compared to controls decreased by 76%, 40%, 38% and 25% in the vessel dilator, atrial natriuretic peptide, kaliuretic peptide and long-acting natriuretic peptide groups respectively (P < 0.05).
CONCLUSIONS: Three of four cardiac hormones synthesized by the atrial natriuretic peptide gene can eliminate human squamous cell lung carcinomas in athymic mice when treated subcutaneously for 4 weeks. The 4th cardiac hormone, i.e. long-acting natriuretic peptide, decreased the volume of one squamous cell lung carcinoma to 2% of that of untreated animals, suggesting that it, too, has beneficial effects on squamous cell lung cancers.

Vesely DL
Metabolic targets of cardiac hormones' therapeutic anti-cancer effects.
Curr Pharm Des. 2010; 16(9):1159-66 [PubMed] Related Publications
The heart is a sophisticated endocrine gland synthesizing a family of peptide hormones by three different genes. These cardiac hormones are stored as 3 prohormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) prohormones. Within the ANP prohormones are 4 peptide hormones, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide (LANP) which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells within 24 hours in cell culture. In vivo these 4 cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, 2/3rds of human breast cancers, and up to 86% of human small-cell lung cancers in athymic mice. Their anticancer mechanism(s) target the Ras-MEK 1/2-ERK 1/2 kinase cascade in cancer cells. These 4 cardiac hormones inhibit up to 95% of the basal activity of Ras, 98% of the phosphorylation of MEK 1/2 and 97% of the activation of basal activity of ERK 1/2. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunfluorescence to inhibit DNA synthesis within cancer cells.

Williams TK, Yeo CJ, Brody J
Does this band make sense? Limits to expression based cancer studies.
Cancer Lett. 2008; 271(1):81-4 [PubMed] Related Publications
Cancer researchers commonly employ reverse transcriptase polymerase chain reaction (RT-PCR) for gene expression analysis of cancer cells. While this technique is facile and reproducible, it is not without limitations. The human genome contains abundant nearly identical sequences (e.g. pseudogenes) to mRNA transcript sequences, which amplify when performing RT-PCR on samples with even trace amounts of genomic DNA. Such sequences include housekeeping transcripts such as beta-actin and GAPDH. This is also true for numerous gene products whose expression is altered in disease states such as cancer (e.g. pp32). Moreover, we describe that amplification of undesirable sequences is not simply avoided by designing primers spanning multiple exons. We also found that template-specific reverse transcriptase reactions lack the specificity necessary to definitively determine the sense or anti-sense orientation of an mRNA transcript. Given the above mentioned caveats and limitations of expression analysis studies, we encourage cancer investigators to test for the existence of intronless genomic sequences that are similar to the specific transcript of the gene being studied. Further, RNA samples should be completely genomic DNA-free prior to performing RT-PCR based assays. Finally, to ensure reliability of RT-PCR or array results, we recommend not utilizing the widely accepted loading controls, GAPDH and/or beta-actin.

Brody JR, Witkiewicz A, Williams TK, et al.
Reduction of pp32 expression in poorly differentiated pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms with moderate dysplasia.
Mod Pathol. 2007; 20(12):1238-44 [PubMed] Related Publications
Nuclear phosphoprotein 32 (pp32) inhibits K-ras induced transformation in experimental models. pp32 mRNA expression correlates with differentiation status in breast and prostate cancers. In this study, we evaluated pp32 protein expression in relation to the differentiation status of pancreatic ductal adenocarcinomas and precursor lesions of the pancreatic cancers. pp32 expression showed strong nuclear staining in normal pancreatic acini and ducts. The intensity of this staining was maintained in pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms with mild dysplasia, well-differentiated adenocarcinomas, and in a subset of moderately differentiated adenocarcinomas. pp32 staining was absent or reduced in poorly differentiated tumors and in intraductal papillary mucinous neoplasms with moderate dysplasia. We validated pp32 expression by a second technique, immunoblot analysis of lysates from resected pancreatic ductal adenocarcinomas and pancreatic cancer cell lines. The well-differentiated pancreatic cancer cell line HPAC expressed high amounts of pp32, as compared to the poorly differentiated pancreatic cancer cell lines MiaPaCa2, Pl19, and Pl21 cells. Artificial introduction of pp32 expression into a poorly differentiated cell line, MiaPaCa2, caused an increase in G1 arrest compared to control cells. On the basis of this study and previous functional work that shows pp32 can inhibit K-ras transformation, we propose that reduction in pp32 expression levels may be a critical event in the progression of pancreatic tumorigenesis in an aggressive subset of pancreatic ductal adenocarcinomas.

Cvetanovic M, Rooney RJ, Garcia JJ, et al.
The role of LANP and ataxin 1 in E4F-mediated transcriptional repression.
EMBO Rep. 2007; 8(7):671-7 [PubMed] Free Access to Full Article Related Publications
The leucine-rich acidic nuclear protein (LANP) belongs to the INHAT family of corepressors that inhibits histone acetyltransferases. The mechanism by which LANP restricts its repression to specific genes is unknown. Here, we report that LANP forms a complex with transcriptional repressor E4F and modulates its activity. As LANP interacts with ataxin 1--a protein mutated in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1)--we tested whether ataxin 1 can alter the E4F-LANP interaction. We show that ataxin 1 relieves the transcriptional repression induced by the LANP-E4F complex by competing with E4F for LANP. These results provide the first functional link, to our knowledge, between LANP and ataxin 1, and indicate a potential mechanism for the transcriptional aberrations observed in SCA1.

Ouellet V, Le Page C, Guyot MC, et al.
SET complex in serous epithelial ovarian cancer.
Int J Cancer. 2006; 119(9):2119-26 [PubMed] Related Publications
With low cure rates but increasing diverse treatment options that provide variable remission times, ovarian cancer is increasingly being recognized as a chronic disease. This reality indicates the need for a better understanding of factors influencing disease progression. In a previous global analysis of gene expression, we identified genes differentially expressed when comparing serous epithelial ovarian tumors of low and high malignant potential (grade 0 vs grade 3). In this analysis, 4 out of 5 members of the SET complex, SET, APE1, NM23 and HMGB2, were highly expressed in invasive grade 3 tumors. To further investigate the expression of these genes and the fifth member of the SET complex (pp32), we performed immunohistochemistry, on a tissue array composed of 235 serous tumors of different grades and disease stages. A significant correlation between expression of all SET complex proteins and the tumor differentiation was observed (p < 0.05). When combining all tumors, overexpression of Nm23 (p = 0.04), Set (p = 0.004) and Ape1 (p = 0.004) was associated with the clinical stage of the disease. No marker by itself was associated with prognosis. The combination of a high level of Nm23 in the context of a low level of Set compared to all other combinations of these markers did confer a better prognosis (p = 0.03). When combined, high expression of Hmgb2 and low expression of Ape1 was also associated with patient prognosis (p = 0.05). These findings suggest that a strategy that sums the activities of different partners within a pathway may be more appropriate in designing nomograms for patient stratification.

Saba SR, Vesely DL
Cardiac natriuretic peptides: hormones with anticancer effects that localize to nucleus, cytoplasm, endothelium, and fibroblasts of human cancers.
Histol Histopathol. 2006; 21(7):775-83 [PubMed] Related Publications
Four cardiac peptide hormones, i.e., vessel dilator, long acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) synthesized by the same gene decrease within 24 hours up to 97% the number of human breast, colon, pancreatic, and prostate adenocarcinoma cells as well as human small-cell and squamous carcinomas of the lung cells. These peptide hormones completely inhibit the growth of human pancreatic adenocarcinomas growing in athymic mice. Immunocytochemical investigations have revealed that LANP, vessel dilator, kaliuretic peptide and ANP localize to the nucleus and cytoplasm of human pancreatic adenocarcinomas, which is consistent with their ability to decrease DNA synthesis in the nucleus of this cancer mediated by the intracellular messenger cyclic GMP. These peptide hormones also localize to the endothelium of capillaries and fibroblasts within these cancers. These are the first growth-inhibiting peptide hormones ever demonstrated to localize to the nucleus. Their ability to decrease the activation of growth promoting substances such as Extracellular Receptor Kinase (ERK)-1/2 and Nuclear Factor Kappa Beta (NFkappaB) suggests that in addition to inhibiting DNA synthesis their ability to decrease the activation of growth promoting substances helps to mediate their ability to inhibit the growth of human cancers.

Vesely DL
Which of the cardiac natriuretic peptides is most effective for the treatment of congestive heart failure, renal failure and cancer?
Clin Exp Pharmacol Physiol. 2006; 33(3):169-76 [PubMed] Related Publications
Cardiac natriuretic peptides consist of a family of six peptide hormones that are synthesised by three separate genes and then stored as three separate prohormones (i.e. 126 amino acid atrial natriuretic peptide (ANP), 108 amino acid B-type natriuretic peptide (BNP) and 103 amino acid C-type natriuretic peptide (CNP) prohormones). The ANP prohormone contains four peptide hormones: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide and ANP. 2. Currently, the only natriuretic peptide available commercially to treat congestive heart failure (CHF) is BNP (Nesiritide/Natrecor; SCIOS, Sunnyvale, CA, USA), which causes a small increase in the urine volume of 90 38 mL/h compared with 67 27 mL/h and no significant natriuresis, but has beneficial haemodynamic effects in acute CHF individuals. These haemodynamic effects probably contribute to the side-effects of BNP in patients with acute CHF with a 27% incidence of hypotension and possibly to 22% worsening of renal function, defined as an increase in serum creatinine of 0.5 mg/dL, associated with a worse prognosis. A review of clinical trials suggests a twofold increased risk of death at 30 days post-nesiritide treatment, a finding that needs further investigation. 3. The best of the natriuretic peptides for treating chronic CHF is the vessel dilator, which increases urinary flow up to 13-fold and sodium excretion up to fourfold, without the previously mentioned side-effects. The natriuretic and diuretic effects of vessel dilators last 6 h, which would allow them to be used on a four times per day basis in treating chronic CHF. 4. Atrial natriuretic peptide does not cause significant improvement in acute renal failure (ARF) in humans. The only natriuretic peptide that significantly improves ARF is the vessel dilator. Even when ARF has been established for 2 days before treatment in an ischaemic ARF animal model, vessel dilator decreases serum creatinine from 8.2 0.5 to 0.98 0.12 mg/dL in 6 days. At day 6 of ARF, mortality decreases to 14% (from 88%) without the vessel dilator. After 6 days of treatment with the vessel dilator, the proximal and distal tubules regenerate. 5. In cancer, vessel dilator, LANP, kaliuretic peptide and ANP at 1 mmol/L, decrease up to 97% of human breast, pancreatic and prostate adenocarcinoma cells, as well as small cell and squamous cell lung cancer cells within 24 h. In vivo, vessel dilator, LANP and kaliuretic peptide completely stop the growth of human pancreatic adenocarcinomas in athymic mice and decrease their tumour volume by 49, 28 and 11%, respectively in 1 week.

Vesely DL
Atrial natriuretic peptides: anticancer agents.
J Investig Med. 2005; 53(7):360-5 [PubMed] Related Publications
Atrial natriuretic peptides (ANPs) consist of a family of six peptide hormones that are synthesized by three different genes and then stored as three different prohormones. Within the 126-amino acid ANP prohormone are four peptide hormones: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, and ANP, whose main known biologic properties are blood pressure regulation and maintenance of plasma volume. The newest discovered property of these peptide hormones is their anticancer effects. Vessel dilator, LANP, kaliuretic peptide, and ANP decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively, within 24 hours at their 1 microM concentrations. Similar results have been found with breast adenocarcinomas, squamous cell lung cancer, and small cell lung cancer cells, each associated with an 83% or greater inhibition of deoxyribonucleic acid (DNA) synthesis by these four peptide hormones. Brain natriuretic peptide has no effects even when increased 100-fold (ie, 100 microM). C-type natriuretic peptide has no effects when increased 10-fold, but when increased 100-fold, it decreases 39% of the cancer cells. At this higher 100 microM concentration, vessel dilator kills 92% of the cancer cells within 24 hours. The four peptide hormones synthesized by the ANP gene given subcutaneously via osmotic pumps in athymic mice with human pancreatic adenocarcinomas completely stop the growth of these adenocarcinomas at 1 week. Vessel dilator, LANP, and kaliuretic peptide within 1 week decrease the volume by 49%, 28%, and 11% of the human pancreatic adenocarcinomas, which, with current anticancer treatment, have a mean survival of only 4 months.

Kochevar GJ, Brody JR, Kadkol SS, et al.
Identification of a functional mutation in pp32r1 (ANP32C).
Hum Mutat. 2004; 23(6):546-51 [PubMed] Related Publications
No mutations or polymorphisms have previously been reported in pp32r1 (ANP32C; GenBank: AF008216.1). pp32r1 is part of the highly conserved ANP32 family, some of whose members are associated with control of histone acetylation, mRNA stability, and specialized forms of apoptosis. Although 87.6% identical at the protein level, pp32r1 is functionally distinct from pp32 (ANP32A) in its failure to suppress oncogenesis in in vitro transformation systems and its tumorigenicity in in vivo assays. The present study found that pp32r1 expression levels vary among human tumor cell lines, with the highest levels found in prostatic adenocarcinoma cell lines. pp32r1 also appears to be polymorphic at nucleotide g.4520 and nucleotide g.4664 in human tobacco-associated oral mucosal lesions, human fibroblast cell lines, and several carcinoma cell lines. PC-3 human prostatic adenocarcinoma cells likewise appear to be polymorphic at these loci, but additionally contain a g.4870T>C transversion mutation. The mutation results in a p.Tyr140His substitution, which lies in a functionally important region of the molecule. In the PC-3 prostate cancer line, the mutation is either homozygous, or hemizygous accompanied by loss of heterozygosity. ACHN cells stably transfected with pp32r1 containing this mutation showed a markedly increased rate of growth. The pp32r1 mutation could thus be causally associated with the neoplastic growth properties of PC-3, and be of potential clinical significance.

Santa-Coloma TA
Anp32e (Cpd1) and related protein phosphatase 2 inhibitors.
Cerebellum. 2003; 2(4):310-20 [PubMed] Related Publications
Mouse Anp32e (Acidic leucine-rich nuclear phosphoprotein 32 family, member e: NM_023210, P97822, formerly Cpd1), a protein identified in postnatal cerebellum by differential display, belongs to the superfamily of leucine rich repeat (LRR) proteins and to the Acidic Nuclear Phosphoprotein 32 (ANP32) family of protein phosphatase 2 (PPP2, formerly PP2A) inhibitors. Two families of PPP2 inhibitor proteins have been described, ANP32 and SET, represented by the human proteins ANP32A (NM_006305, formerly LANP, PP32, I1PPP2, PHAPI, MAPM, mapmodulin) and SET (NM_003011, formerly PHAPII, 2PPP2, I2PPP2, TAF-1BETA). Besides their common PPP2 inhibitor activity, described several years ago, these nucleo-cytoplasmic shuttling phosphoproteins have additional and very important functions recently reported. In HeLa cells, ANP32A, SET (isoforms A and B) and ANP32B (APRIL), form a multi-subunit heterocomplex with ELAVL1 (NM_001419, formerly HuR), a protein that stabilizes short-lived mRNAs containing AU-rich elements (AREs). A similar heterocomplex, formed by SET (A and B) and ANP32A as major subunits, possess histone acetyltransferase inhibitory activity (INHAT), and have a role in chromatin remodeling and transcriptional regulation (histone code). The possible roles of these multifunctional proteins are discussed here, with emphasis on mouse Anp32e and the cerebellar tissue.

Brody JR, Kadkol SS, Hauer MC, et al.
pp32 reduction induces differentiation of TSU-Pr1 cells.
Am J Pathol. 2004; 164(1):273-83 [PubMed] Free Access to Full Article Related Publications
pp32 (ANP32A) is a nuclear phosphoprotein expressed as a nonmutated form in self-renewing cell populations and neoplastic cells. Mechanistically, pp32 may regulate pathways important in the process of differentiation as part of separate complexes inhibiting histone acetylation and regulating immediate-early and cytokine mRNA stability. Prostatic adenocarcinomas express pp32 in a differentiation related manner-well-differentiated tumors express lower levels of pp32 than poorly differentiated tumors. In benign prostate, pp32 is expressed in basal cells but not in terminally differentiated glandular cells. Based on these observations, we hypothesized that reduction of pp32 expression might be an important differentiation signal. We used anti-sense pp32 and RNAi transfection to study the effects of reduced pp32 expression in the TSU-Pr1 carcinoma cell line. pp32 reduction induced TSU-Pr1 cells to differentiate into neuronal-like cells with associated inhibition of growth. Reduction of pp32 and consequent differentiation were accompanied by a marked reduction in expression of SET, which complexes with pp32, by a marked change in acetylation status of histone H4, and by further differential expression of genes in differentiation pathways. Thus, reduction of pp32 in the undifferentiated TSU-Pr1 neoplastic cell line induces differentiation and thus may be an element of a differentiation control pathway in both normal and neoplastic cells.

Kadkol SS, El Naga GA, Brody JR, et al.
Expression of pp32 gene family members in breast cancer.
Breast Cancer Res Treat. 2001; 68(1):65-73 [PubMed] Related Publications
The pp32 gene family consists of at least three closely related members, pp32, pp32r1 and pp32r2. In spite of a high degree of identity at the nucleotide level, pp32 functionally behaves as a tumor suppressor where as pp32r1 and pp32r2 are pro-oncogenic. The purpose of this pilot study was to determine pp32-related expression and whether alternative gene use among the pp32 family members occurred in human breast cancer. As a first step, in situ hybridization with a riboprobe capable of hybridizing with all the three members showed abundant pp32-related mRNA in benign ducts and acini and in infiltrating ductal carcinomas. A total of 100/102 cases were positive. Further, a detailed molecular analysis by RT-PCR, cloning, and sequencing was performed in five frozen infiltrating breast carcinomas and matched benign breast tissues. Oncogenic pp32r1 (5/5) and pp32r2 (3/5) expression was observed in carcinomas where as benign breast tissues expressed pp32. 4/5 carcinomas continued to express pp32 but one was devoid of pp32 expression. These results suggest that alternative expression of pp32 family members may be common in human breast cancer and the analysis of the profile of pp32-related expression might be helpful in understanding the role of these genes in breast cancer pathogenesis.

Bai J, Brody JR, Kadkol SS, Pasternack GR
Tumor suppression and potentiation by manipulation of pp32 expression.
Oncogene. 2001; 20(17):2153-60 [PubMed] Related Publications
Alternative use of genes of the closely-related pp32 family is a common occurrence in human prostate cancer. pp32r1 and pp32r2, the oncogenic members of the pp32 family, are expressed in prostatic adenocarcinoma, while adjacent benign prostate continues to express pp32. This study focuses upon the role of pp32 in tumor suppression. We demonstrate that antisense inhibition of pp32 in NIH3T3 cells leads to a variety of phenotypic changes associated with transformation including reduced serum dependence and loss of contact inhibition. NIH3T3 cells with antisense-inhibited pp32 are not tumorigenic, but are markedly more susceptible to oncogenic stimuli such as ras. In contrast, constitutive expression of pp32 abolishes ras mediated transformation in vitro and tumorigenesis in vivo. These data demonstrate, from the functional aspect, that pp32 acts as a tumor suppressor. Furthermore, inactivation of pp32 function through alternative gene use may be a critical event in tumor evolution and progression.

Kadkol SS, Brody JR, Pevsner J, et al.
Modulation of oncogenic potential by alternative gene use in human prostate cancer.
Nat Med. 1999; 5(3):275-9 [PubMed] Related Publications
Only a small percentage of primary prostate cancers have genetic changes. In contrast, nearly 90% of clinically significant human prostate cancers seems to express high levels of the nuclear phosphoprotein pp32 by in situ hybridization. Because pp32 inhibits oncogene-mediated transformation, we investigated its paradoxical expression in cancer by comparing the sequence and function of pp32 species from paired benign prostate tissue and adjacent prostatic carcinoma from three patients. Here we demonstrate that pp32 is expressed in benign prostatic tissue, but pp32r1 and pp32r2, closely-related genes located on different chromosomes, are expressed in prostate cancer. Although pp32 is a tumor suppressor, pp32r1 and pp32r2 are tumorigenic. Alternative use of the pp32, pp32r1 and pp32r2 genes may modulate the oncogenic potential of human prostate cancer.

Gusev Y, Romantsev FE, Chen TT, et al.
pp32 overexpression induces nuclear pleomorphism in rat prostatic carcinoma cells.
Cell Prolif. 1996; 29(12):643-53 [PubMed] Related Publications
Nuclear pleomorphism is an important diagnostic factor in tumour pathology. Traditionally, nuclear pleomorphism is evaluated qualitatively or semiquantitatively, often as a component of tumour grade; the molecular basis of nuclear pleomorphism, however, remains unclear. In this study, we investigated the quantitative effects on nuclear morphology of overexpressing pp32, a recently described nuclear phosphoprotein highly expressed in self-renewing and neoplastic cell populations. Assessment of Feulgen-stained transfected and control lines of AT3.1, a rat prostatic carcinoma cell line, using a computerized Cellular Image Analysis System (BD CAS-200) showed that stable overexpression of human pp32 in AT3.1 cells is accompanied by marked increases in the coefficient of variation of nuclear shape, nuclear size and chromatin textures but not in DNA content. In contrast, stable transfection with control vector, with ras, or with bcl-2 failed to affect nuclear morphology. Cell cycle analysis further showed that pp32-related increases in variation of nuclear structure manifested principally in G1. These studies suggest that pp32 plays a role either directly or indirectly in the control of nuclear shape of G1 cells.

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