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Gene Review

PAPOLA  -  poly(A) polymerase alpha

Homo sapiens

Synonyms: PAP, PAP-alpha, Poly(A) polymerase alpha, Polynucleotide adenylyltransferase alpha
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Disease relevance of PAPOLA


Psychiatry related information on PAPOLA

  • The measurement of transmural values allowed a reliable assessment of PAP changes occurring during apneas, and different degrees of such changes shown by different patients may be related to a host of factors relevant to wakefulness and sleep, including individual responsivity to hypoxic stimulus [4].
  • This review presents the possible involvement of 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase in the etiology of bipolar disorder and the mechanism of action of Li [5].
  • Physiological data (VO2peak, height, and weight), psychological data (physical self-perception profile subscale scores), information about physical activity participation (PAP, d x wk(-1)) and qualitative impressions (QI) of the program were collected pre- and post-intervention [6].

High impact information on PAPOLA

  • Domains are identified in both proteins whose removal uncouples the polyadenylation activity of mammalian PAP from its inhibition via RNA-bound U1A protein [7].
  • Monospecific rabbit antiserums to PAPP-A, PAPP-C and hCS all stained the trophoblast cytoplasm equivalently in a continuous layer, usggesting that the same trophoblast cells synthesize all three pregnancy proteins [8].
  • This suggests that the carboxy-terminal region of PAP with which it interacts is involved not only in U1A autoregulation but also in the coupling of splicing and 3'-end formation [9].
  • Conservation of the U1 70K inhibitory domains suggests that polyadenylation regulation via PAP inhibition may be more widespread than previously thought [10].
  • U1 snRNP binding to the 5' splice site results in inhibition of polyadenylation via a direct interaction with poly(A) polymerase (PAP) [10].

Chemical compound and disease context of PAPOLA

  • We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens [11].
  • HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy [12].
  • While neither low nor high doses of DHAS and PAP exerted any significant influence on the incidence of ductal lesions including carcinomas, the high dose of DHAS (350 mg/kg body wt) and a both low (90 mg/kg) and high (180 mg/kg) doses of PAP reduced the mean numbers of pancreatic ductal adenocarcinomas [13].
  • Using the PAP method, localization of the calcineurin in formalin-fixed, paraffin-embedded tissues were studied in 65 human intracranial neoplasms, and in 11 human extracranial neoplasms [14].
  • In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased [15].

Biological context of PAPOLA

  • In the experiments described here, we undertook a genetic approach in chicken DT40 cells to study the function of PAP phosphorylation [16].
  • We propose that the lower growth rate is due to the failure of hyperphosphorylation and thus M-phase inactivation of cdk- PAP [16].
  • Vertebrate poly(A) polymerase (PAP) contains a catalytic domain and a C-terminal Ser-Thr-rich regulatory region [16].
  • The binding of 14-3-3epsilon to PAP inhibits the polyadenylation activity of PAP in vitro, and overexpression of 14-3-3epsilon leads to a shorter poly(A) mRNA tail in vivo [17].
  • Deletion analysis of PAP suggests that PAP contains multiple binding sites for 14-3-3epsilon [17].

Anatomical context of PAPOLA

  • Mucosal PAP smears show lack of epithelial maturation, cytoplasmic vacuoles and inclusions, and individual cell dyskeratosis [18].
  • In contrast, correlations were noted between PS-positive erythrocytes and F1.2 (P <.0002), D-dimer (P <.000002), and PAP (P <.01) [19].
  • HIP/PAP belongs to the family of C-type lectins and acts as an adhesion molecule for hepatocytes [20].
  • The EBV-producing B lymphoblastoid cell line B95-8 was found to efficiently activate the alternative C pathway whether assessed with Mg-EGTA-treated human serum or with mixtures of the purified proteins of the pathway (PAP) [21].
  • Lymphocytes from islet infiltrates and pancreatic lymph nodes from 7- to 10-week-old NOD mice were used to establish an HIP/PAP-specific I-A(g7)-restricted T-cell line, termed WY1, that also responded to mouse islets [22].

Associations of PAPOLA with chemical compounds


Physical interactions of PAPOLA

  • The NMR structure of the 38 kDa complex formed between two U1A molecules and PIE RNA shows that binding cooperativity depends on helix C located at the end of the RNA-binding domain and just adjacent to the PAP-interacting domain of U1A [23].
  • Here we show that cyclin B(1) binds PAP directly, and we demonstrate further that this interaction is mediated by a stretch of amino acids in PAP with homology to the cyclin recognition motif (CRM), a sequence previously shown in several cell cycle regulators to target specifically G(1)-phase-type cyclins [26].

Regulatory relationships of PAPOLA

  • Our data not only support the notion that PAP is directly regulated by cyclin-dependent kinases throughout the cell cycle but also introduce a novel type of CRM that functionally interacts with both G(1)- and G(2)-type cyclins in an unexpected way [26].

Other interactions of PAPOLA

  • We showed previously that p34(cdc2)/cyclin B (MPF) hyperphosphorylates poly(A) polymerase (PAP) during M-phase of the cell cycle, causing repression of its enzymatic activity [27].
  • In vitro the NS1A protein inhibits the ability of PABII to stimulate the processive synthesis of long poly(A) tails catalyzed by poly(A) polymerase (PAP) [28].
  • While higher concentrations of PAP's CRM block PAP-cyclin binding and phosphorylation, lower concentrations induce dramatic stimulation of both activities [26].

Analytical, diagnostic and therapeutic context of PAPOLA

  • Intriguingly, Northern blot analysis demonstrated that each PAP displayed distinct mRNA splice variants, and both PAP mRNAs were significantly overexpressed in human cancer cells compared to expression in normal or virally transformed cells [29].
  • These biodegradable PAP copolymers with electroactive function thus possess the properties that would be potentially used as scaffold materials for neuronal or cardiovascular tissue engineering [30].
  • Frozen sections of human placenta were examined for the presence of four human pregnancy proteins, pregnancy-associated plasma proteins A and C (PAPP-A and PAPP-C), human chorionic somatomammotropin (hCS), and pregnancy zone protein (PZP), by the indirect immunofluorescence technique [8].
  • The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases [31].
  • The complex formation was demonstrated by the binding of fluid-phase IgG from normal adults and the same TTP patient after recovery to adsorbed PAP by using an enzyme-linked immunosorbent assay [32].


  1. Multiple forms of poly(A) polymerases in human cells. Thuresson, A.C., Aström, J., Aström, A., Grönvik, K.O., Virtanen, A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Hypophosphorylation of poly(A) polymerase and increased polyadenylation activity are associated with human immunodeficiency virus type 1 Vpr expression. Mouland, A.J., Coady, M., Yao, X.J., Cohen, E.A. Virology (2002) [Pubmed]
  3. Mutations in MKKS cause Bardet-Biedl syndrome. Slavotinek, A.M., Stone, E.M., Mykytyn, K., Heckenlively, J.R., Green, J.S., Heon, E., Musarella, M.A., Parfrey, P.S., Sheffield, V.C., Biesecker, L.G. Nat. Genet. (2000) [Pubmed]
  4. Transmural pressure measurements. Importance in the assessment of pulmonary hypertension in obstructive sleep apneas. Marrone, O., Bellia, V., Ferrara, G., Milone, F., Romano, L., Salvaggio, A., Stallone, A., Bonsignore, G. Chest (1989) [Pubmed]
  5. Possible role of 3'(2')-phosphoadenosine-5'-phosphate phosphatase in the etiology and therapy of bipolar disorder. Agam, G., Shaltiel, G. Prog. Neuropsychopharmacol. Biol. Psychiatry (2003) [Pubmed]
  6. Daughters and mothers exercising together (DAMET): a 12-week pilot project designed to improve physical self-perception and increase recreational physical activity. Ransdell, L.B., Dratt, J., Kennedy, C., O'Neill, S., DeVoe, D. Women & health. (2001) [Pubmed]
  7. The human U1A snRNP protein regulates polyadenylation via a direct interaction with poly(A) polymerase. Gunderson, S.I., Beyer, K., Martin, G., Keller, W., Boelens, W.C., Mattaj, L.W. Cell (1994) [Pubmed]
  8. Placental localization of human pregnancy--associated plasma proteins. Lin, T.M., Halbert, S.P. Science (1976) [Pubmed]
  9. Involvement of the carboxyl terminus of vertebrate poly(A) polymerase in U1A autoregulation and in the coupling of splicing and polyadenylation. Gunderson, S.I., Vagner, S., Polycarpou-Schwarz, M., Mattaj, I.W. Genes Dev. (1997) [Pubmed]
  10. U1 snRNP inhibits pre-mRNA polyadenylation through a direct interaction between U1 70K and poly(A) polymerase. Gunderson, S.I., Polycarpou-Schwarz, M., Mattaj, I.W. Mol. Cell (1998) [Pubmed]
  11. Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide. Uckun, F.M., Chelstrom, L.M., Finnegan, D., Tuel-Ahlgren, L., Manivel, C., Irvin, J.D., Myers, D.E., Gunther, R. Blood (1992) [Pubmed]
  12. Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice. Lieu, H.T., Simon, M.T., Nguyen-Khoa, T., Kebede, M., Cortes, A., Tebar, L., Smith, A.J., Bayne, R., Hunt, S.P., Br??chot, C., Christa, L. Hepatology (2006) [Pubmed]
  13. Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl)amine in hamsters. Tsutsumi, M., Noguchi, O., Okita, S., Horiguchi, K., Kobayashi, E., Tamura, K., Tsujiuchi, T., Denda, A., Konishi, Y., Iimura, K. Carcinogenesis (1995) [Pubmed]
  14. Calcineurin as a neuronal marker of human brain tumors. Goto, S., Matsukado, Y., Mihara, Y., Inoue, N., Miyamoto, E. Brain Res. (1986) [Pubmed]
  15. Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio. Kario, K., Matsuo, T., Kodama, K., Matsuo, M., Yamamoto, K., Kobayashi, H. Haemostasis (1992) [Pubmed]
  16. Deregulation of poly(A) polymerase interferes with cell growth. Zhao, W., Manley, J.L. Mol. Cell. Biol. (1998) [Pubmed]
  17. Regulation of poly(A) polymerase by 14-3-3epsilon. Kim, H., Lee, J.H., Lee, Y. EMBO J. (2003) [Pubmed]
  18. Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation. Witkop, C.J., White, J.G., King, R.A., Dahl, M.V., Young, W.G., Sauk, J.J. Am. J. Hum. Genet. (1979) [Pubmed]
  19. Thrombophilia in sickle cell disease: the red cell connection. Setty, B.N., Rao, A.K., Stuart, M.J. Blood (2001) [Pubmed]
  20. HIP/PAP gene, encoding a C-type lectin overexpressed in primary liver cancer, is expressed in nervous system as well as in intestine and pancreas of the postimplantation mouse embryo. Lasserre, C., Colnot, C., Bréchot, C., Poirier, F. Am. J. Pathol. (1999) [Pubmed]
  21. Activation of the alternative complement pathway by EBV and the viral envelope glycoprotein, gp350. Mold, C., Bradt, B.M., Nemerow, G.R., Cooper, N.R. J. Immunol. (1988) [Pubmed]
  22. A Reg family protein is overexpressed in islets from a patient with new-onset type 1 diabetes and acts as T-cell autoantigen in NOD mice. Gurr, W., Yavari, R., Wen, L., Shaw, M., Mora, C., Christa, L., Sherwin, R.S. Diabetes (2002) [Pubmed]
  23. The NMR structure of the 38 kDa U1A protein - PIE RNA complex reveals the basis of cooperativity in regulation of polyadenylation by human U1A protein. Varani, L., Gunderson, S.I., Mattaj, I.W., Kay, L.E., Neuhaus, D., Varani, G. Nat. Struct. Biol. (2000) [Pubmed]
  24. Crystal structure of the human estrogen sulfotransferase-PAPS complex: evidence for catalytic role of Ser137 in the sulfuryl transfer reaction. Pedersen, L.C., Petrotchenko, E., Shevtsov, S., Negishi, M. J. Biol. Chem. (2002) [Pubmed]
  25. A novel mammalian lithium-sensitive enzyme with a dual enzymatic activity, 3'-phosphoadenosine 5'-phosphate phosphatase and inositol-polyphosphate 1-phosphatase. López-Coronado, J.M., Bellés, J.M., Lesage, F., Serrano, R., Rodríguez, P.L. J. Biol. Chem. (1999) [Pubmed]
  26. Poly(A) polymerase phosphorylation is dependent on novel interactions with cyclins. Bond, G.L., Prives, C., Manley, J.L. Mol. Cell. Biol. (2000) [Pubmed]
  27. Inhibition of poly(A) polymerase requires p34cdc2/cyclin B phosphorylation of multiple consensus and non-consensus sites. Colgan, D.F., Murthy, K.G., Zhao, W., Prives, C., Manley, J.L. EMBO J. (1998) [Pubmed]
  28. Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3'-end processing machinery. Chen, Z., Li, Y., Krug, R.M. EMBO J. (1999) [Pubmed]
  29. Identification and functional characterization of neo-poly(A) polymerase, an RNA processing enzyme overexpressed in human tumors. Topalian, S.L., Kaneko, S., Gonzales, M.I., Bond, G.L., Ward, Y., Manley, J.L. Mol. Cell. Biol. (2001) [Pubmed]
  30. Synthesis and characterization of electroactive and biodegradable ABA block copolymer of polylactide and aniline pentamer. Huang, L., Hu, J., Lang, L., Wang, X., Zhang, P., Jing, X., Wang, X., Chen, X., Lelkes, P.I., Macdiarmid, A.G., Wei, Y. Biomaterials (2007) [Pubmed]
  31. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. Kitamura, T., Tanaka, N., Watanabe, J., Uchida, n.u.l.l., Kanegasaki, S., Yamada, Y., Nakata, K. J. Exp. Med. (1999) [Pubmed]
  32. Platelet-agglutinating protein P37 from a thrombotic thrombocytopenic purpura plasma forms a complex with human immunoglobulin G. Siddiqui, F.A., Lian, E.C. Blood (1988) [Pubmed]
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