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Gene Review

RNASE1  -  ribonuclease, RNase A family, 1 (pancreatic)

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Disease relevance of RNASE1

  • Human melanoma cells established in culture were extremely susceptible to BS RNase, administered in concentrations ranging from 1-100 microg/ml [1].
  • The effect of BS RNase on mouse seminoma was well pronounced [1].
  • Like naturally dimeric seminal RNase, at equilibrium the mutant dimeric RNase A adopted two quaternary structures (one with an exchange of the N-terminal segments between partner subunits, the other with no exchange) and displayed a selective toxicity for malignant cells, absent in the monomeric, parent protein [2].
  • This cDNA was inserted into expression plasmids that then directed the production of RNase A in Saccharomyces cerevisiae (fused to a modified alpha-factor leader sequence) or Escherichia coli (fused to the pelB signal sequence) [3].
  • To learn more about its antitumor effect we tested BS RNase on the growth of 16 cell lines derived from patients with various hematological malignancies [4].

High impact information on RNASE1

  • Using defined components, the binding of ribonuclease B (RNase B) Man7-Man9 glycoforms to the luminal domain of calnexin was observed in vitro only if RNase B was monoglucosylated [5].
  • We present here the crystal structure at 2.5 A resolution of the complex between ribonuclease A and ribonuclease inhibitor, a protein built entirely of leucine-rich repeats [6].
  • The unusual non-globular structure of ribonuclease inhibitor, its solvent-exposed parallel beta-sheet and the conformational flexibility of the structure are used in the interaction; they appear to be the principal reasons for the effectiveness of leucine-rich repeats as protein-binding motifs [6].
  • Incubation of ribonuclease with 0.1M mercaptoethanol at pH 8.5 can increase the enzyme's hydrolytic activity toward cytidine 2',3'-monophosphate (cyclic CMP) under standard assay conditions [7].
  • Enhancement of bovine pancreatic ribonuclease activity by mercaptoethanol [7].

Chemical compound and disease context of RNASE1


Biological context of RNASE1


Anatomical context of RNASE1

  • We demonstrate that recombinant angiogenin functions as a cytotoxic tRNA-specific RNase in cell-free lysates and when injected into Xenopus oocytes [14].
  • Human angiogenin is a blood vessel inducing protein whose primary structure displays 33% identity to that of bovine pancreatic ribonuclease A (RNase A) [15].
  • The structures presented here provide a promising starting point for the rational design of tight-binding RNase inhibitors, which may be used as therapeutic agents in restraining the ribonucleolytic activities of RNase homologues such as angiogenin, eosinophil-derived neurotoxin, and eosinophil cationic protein [17].
  • In contrast to RNase A, which was ineffective in all biological activities tested, angiogenin suppressed significantly the proliferation of human lymphocytes stimulated by phytohemagglutinin or concanavalin A or by allogenic human lymphocytes (mixed lymphocyte culture) [18].
  • The ribonuclease activities of all three forms were equivalent to or higher than that of dimeric BS-RNase isolated from bull seminal plasma [19].

Associations of RNASE1 with chemical compounds

  • The thermodynamic consequences of the progressive introduction of these four residues into RNase A polypeptide chain have been studied by comparing the temperature- and urea-induced denaturation of three mutants of RNase A with that of a stable monomeric derivative of BS-RNase [20].
  • Thus, the six-membered and five-membered rings of both adenines are reversed with respect to the others but nonetheless engage in extensive interactions with the residues that form the B2 purine binding site of RNase A [17].
  • Crystal structures of ribonuclease A complexes with 5'-diphosphoadenosine 3'-phosphate and 5'-diphosphoadenosine 2'-phosphate at 1.7 A resolution [17].
  • The effects of Phe versus Ala substitutions show that the key residue Tyr434 interacts with both ligands primarily through its phenyl ring; for Tyr437, the OH group forms the important contacts with RNase A, whereas the phenyl group interacts with Ang [21].
  • The two uridilyl inhibitors bind similarly with the uridine moiety in the B1 subsite but the placement of a different phosphate group in P1 (2' versus 3') has significant implications on their potency against RNase A [22].

Physical interactions of RNASE1

  • The difference spectra of bovine kidney RNase K2 induced upon binding with nucleotides markedly differ from those of bovine pancreatic RNase [23].

Enzymatic interactions of RNASE1

  • Angiogenin catalyzes limited cleavage of 18S and 28S ribosomal RNA and is several orders of magnitude less potent than RNase A toward conventional substrates [15].
  • The substrate specificity of the ubiquitin (Ub) conjugation system was explored with regard to recognition of unfolded conformation and/or oxidized methionine residues in six derivatives of bovine RNase A [24].

Regulatory relationships of RNASE1


Other interactions of RNASE1

  • From ribonuclease A toward bovine seminal ribonuclease: a step by step thermodynamic analysis [20].
  • Comparison of the amino acid sequences of cyanogen bromide fragments and the pyroglutaminase-treated N-terminal fragment of lactogenin with the sequence of bovine liver RNase (RNase BL4) revealed identity in residues 3-22, 24, 26-27, 37, 41-44, 46-50, 54, 56, 63, 72-80, and 83 [29].
  • A ribonuclease (RNAase BSD) isolated by us earlier from bovine seminal plasma by DNA-affinity chromatography is shown to be homogeneous on polyacrylamide gel electrophoresis, analytical ultracentrifuge and high performance liquid chromatography [30].
  • Using the RNase protection assay, we found that the application of a cyclic biaxial strain to cells induced a 2.5- to 4-fold increase in IGF-I mRNA levels after 8 h and an even greater increase after 16-24 h of stretch [31].
  • A mRNA species encoding a putative variant cGS PDE isoform was detected by RNase protection [32].

Analytical, diagnostic and therapeutic context of RNASE1


  1. Antitumor action of bovine seminal ribonuclease. Cytostatic effect on human melanoma and mouse seminoma. Poucková, P., Soucek, J., Jelínek, J., Zadinová, M., Hlousková, D., Polívková, J., Navrátil, L., Cinátl, J., Matousek, J. Neoplasma (1998) [Pubmed]
  2. Ribonuclease A can be transformed into a dimeric ribonuclease with antitumor activity. Di Donato, A., Cafaro, V., D'Alessio, G. J. Biol. Chem. (1994) [Pubmed]
  3. Engineering ribonuclease A: production, purification and characterization of wild-type enzyme and mutants at Gln11. delCardayré, S.B., Ribó, M., Yokel, E.M., Quirk, D.J., Rutter, W.J., Raines, R.T. Protein Eng. (1995) [Pubmed]
  4. Antitumor action of bovine seminal ribonuclease. Soucek, J., Poucková, P., Matousek, J., Stockbauer, P., Dostál, J., Zadinová, M. Neoplasma (1996) [Pubmed]
  5. Conformation-independent binding of monoglucosylated ribonuclease B to calnexin. Zapun, A., Petrescu, S.M., Rudd, P.M., Dwek, R.A., Thomas, D.Y., Bergeron, J.J. Cell (1997) [Pubmed]
  6. A structural basis of the interactions between leucine-rich repeats and protein ligands. Kobe, B., Deisenhofer, J. Nature (1995) [Pubmed]
  7. Enhancement of bovine pancreatic ribonuclease activity by mercaptoethanol. Watkins, J.B., Benz, F.W. Science (1978) [Pubmed]
  8. A study of the intracellular routing of cytotoxic ribonucleases. Wu, Y., Saxena, S.K., Ardelt, W., Gadina, M., Mikulski, S.M., De Lorenzo, C., D'Alessio, G., Youle, R.J. J. Biol. Chem. (1995) [Pubmed]
  9. Ribonuclease A as a substrate of the protease from human immunodeficiency virus-1. Hui, J.O., Tomasselli, A.G., Zürcher-Neely, H.A., Heinrikson, R.L. J. Biol. Chem. (1990) [Pubmed]
  10. Determinants of the hierarchy of humoral immune responsiveness during ontogeny. Sherwin, W.K., Rowlands, D.T. J. Immunol. (1975) [Pubmed]
  11. Capillary and slab gel electrophoresis profiling of oligosaccharides. Guttman, A., Starr, C. Electrophoresis (1995) [Pubmed]
  12. Purification and characterization of a peptide essential for formation of streptolysin S by Streptococcus pyogenes. Akao, T., Takahashi, T., Kobashi, K. Infect. Immun. (1992) [Pubmed]
  13. Molecular determinants in the plasma clearance and tissue distribution of ribonucleases of the ribonuclease A superfamily. Vasandani, V.M., Wu, Y.N., Mikulski, S.M., Youle, R.J., Sung, C. Cancer Res. (1996) [Pubmed]
  14. Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. Saxena, S.K., Rybak, S.M., Davey, R.T., Youle, R.J., Ackerman, E.J. J. Biol. Chem. (1992) [Pubmed]
  15. A covalent angiogenin/ribonuclease hybrid with a fourth disulfide bond generated by regional mutagenesis. Harper, J.W., Vallee, B.L. Biochemistry (1989) [Pubmed]
  16. A hybrid of bovine pancreatic ribonuclease and human angiogenin: an external loop as a module controlling substrate specificity? Allemann, R.K., Presnell, S.R., Benner, S.A. Protein Eng. (1991) [Pubmed]
  17. Crystal structures of ribonuclease A complexes with 5'-diphosphoadenosine 3'-phosphate and 5'-diphosphoadenosine 2'-phosphate at 1.7 A resolution. Leonidas, D.D., Shapiro, R., Irons, L.I., Russo, N., Acharya, K.R. Biochemistry (1997) [Pubmed]
  18. Immunosuppressive activity of angiogenin in comparison with bovine seminal ribonuclease and pancreatic ribonuclease. Matousek, J., Soucek, J., Ríha, J., Zankel, T.R., Benner, S.A. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (1995) [Pubmed]
  19. Bovine seminal ribonuclease produced from a synthetic gene. Kim, J.S., Raines, R.T. J. Biol. Chem. (1993) [Pubmed]
  20. From ribonuclease A toward bovine seminal ribonuclease: a step by step thermodynamic analysis. Catanzano, F., Graziano, G., Cafaro, V., D'Alessio, G., Di Donato, A., Barone, G. Biochemistry (1997) [Pubmed]
  21. Superadditive and subadditive effects of "hot spot" mutations within the interfaces of placental ribonuclease inhibitor with angiogenin and ribonuclease A. Chen, C.Z., Shapiro, R. Biochemistry (1999) [Pubmed]
  22. High-resolution crystal structures of ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-based design of ribonucleolytic inhibitors. Leonidas, D.D., Chavali, G.B., Oikonomakos, N.G., Chrysina, E.D., Kosmopoulou, M.N., Vlassi, M., Frankling, C., Acharya, K.R. Protein Sci. (2003) [Pubmed]
  23. The difference spectra of bovine kidney RNase K2 induced upon binding with nucleotides markedly differ from those of bovine pancreatic RNase. Irie, M., Ohgi, K., Nitta, R., Ikeda, M., Ueno, M. J. Biochem. (1989) [Pubmed]
  24. Recognition of modified forms of ribonuclease A by the ubiquitin system. Dunten, R.L., Cohen, R.E. J. Biol. Chem. (1989) [Pubmed]
  25. Effect of wheat leaf ribonuclease on tumor cells and tissues. Skvor, J., Lipovová, P., Poucková, P., Soucek, J., Slavík, T., Matousek, J. Anticancer Drugs (2006) [Pubmed]
  26. Insulin-like growth factors (IGFs) and IGF binding protein-3 display disulfide isomerase activity. Koedam, J.A., van den Brande, J.L. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  27. Transfer RNA is required for conjugation of ubiquitin to selective substrates of the ubiquitin- and ATP-dependent proteolytic system. Ferber, S., Ciechanover, A. J. Biol. Chem. (1986) [Pubmed]
  28. Immobilized carboxypeptidase A as a probe for studying the thermally induced unfolding of bovine pancreatic ribonuclease. Burgess, A.W., Weinstein, L.I., Gabel, D., Scheraga, H.A. Biochemistry (1975) [Pubmed]
  29. Isolation and characterization of angiogenin-1 and a novel protein designated lactogenin from bovine milk. Ye, X.Y., Cheng, K.J., Ng, T.B. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  30. Identity of the ribonuclease from bovine seminal plasma with ribonuclease BS-1, and its sensitivity to polyvinyl sulphate. Ramakrishna, T., Pandit, M.W. J. Biochem. (1984) [Pubmed]
  31. Mechanical regulation of IGF-I and IGF-binding protein gene transcription in bladder smooth muscle cells. Chaqour, B., Han, J.S., Tamura, I., Macarak, E. J. Cell. Biochem. (2002) [Pubmed]
  32. Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. Sonnenburg, W.K., Mullaney, P.J., Beavo, J.A. J. Biol. Chem. (1991) [Pubmed]
  33. Site-specific mutagenesis reveals differences in the structural bases for tight binding of RNase inhibitor to angiogenin and RNase A. Chen, C.Z., Shapiro, R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  34. Oligomerization of ribonuclease A: two novel three-dimensional domain-swapped tetramers. Gotte, G., Libonati, M. J. Biol. Chem. (2004) [Pubmed]
  35. Contribution of the active site histidine residues of ribonuclease A to nucleic acid binding. Park, C., Schultz, L.W., Raines, R.T. Biochemistry (2001) [Pubmed]
  36. Origin of the catalytic activity of bovine seminal ribonuclease against double-stranded RNA. Opitz, J.G., Ciglic, M.I., Haugg, M., Trautwein-Fritz, K., Raillard, S.A., Jermann, T.M., Benner, S.A. Biochemistry (1998) [Pubmed]
  37. PEG chains increase aspermatogenic and antitumor activity of RNase A and BS-RNase enzymes. Matousek, J., Poucková, P., Soucek, J., Skvor, J. Journal of controlled release : official journal of the Controlled Release Society. (2002) [Pubmed]
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