Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1983 Aug;80(15):4609–4613. doi: 10.1073/pnas.80.15.4609

(2'-5')Oligoadenylate in rat liver: modulation after partial hepatectomy.

M Etienne-Smekens, P Vandenbussche, J Content, J E Dumont
PMCID: PMC384093  PMID: 6308630

Abstract

(2'-5')Oligoadenylate synthetase [(2'-5')A synthetase], which synthesizes a series of oligoadenylates ppp-(A2'p)n5'A [collectively referred to as (2'-5')A], has been described previously in rat liver cells, where its concentration varied with the growth status of this organ--i.e., it decreased during the early phase of rat liver regeneration after partial hepatectomy. Because double-stranded RNA, the only known activator of this enzyme, has been detected in rat liver nuclei, (2'-5')A synthesis could occur in this tissue in vivo. Analysis of rat liver cell extract after HPLC by the endonuclease-based radiobinding assay revealed several components with retention times similar to (2'-5')A trimer- and tetramer-like material. A further characterization of these compounds by their susceptibility to alkaline phosphatase and snake venom phosphodiesterase, their resistance to micrococcal nuclease, and their ability to activate an endonuclease indicated the natural occurrence of oligonucleotides indistinguishable from authentic (2'-5')A in rat liver cells. Using the combination of the radiobinding assay and a simplified (2'-5')A extraction procedure that does not involve HPLC, we further show that the early drop of (2'-5')A synthetase activity during rat liver regeneration was accompanied by a similar decrease in intracellular (2'-5')A concentration. The three characteristic phases of the (2'-5')A synthetase kinetics during the first 40 hr of liver regeneration were mimicked by the kinetics of the synthesis of the (2'-5')A oligonucleotides themselves: between 6 and 20 hr after hepatectomy, there was a sharp decrease in (2'-5')A concentration; between 20 and 24 hr, the concentration of (2'-5')A reached a minimum; at 36 hr or after the first wave of DNA synthesis (the major event of liver regeneration), the (2'-5')A concentration returned to normal. In this characterization of the (2'-5')A oligonucleotide family in a functional tissue of an animal that had not been previously treated with interferon or infected with virus, the data are compatible with a physiological role of the (2'-5')A system acting as an intracellular component of the regulatory mechanisms leading to cell proliferation or differentiation.

Full text

PDF
4611

Images in this article

4611Image
on p.4611

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baglioni C., Minks M. A., Maroney P. A. Interferon action may be mediated by activation of a nuclease by pppA2'p5'A2'p5'A. Nature. 1978 Jun 22;273(5664):684–687. doi: 10.1038/273684a0. [DOI] [PubMed] [Google Scholar]
  2. Baglioni C., Nilsen T. W., Maroney P. A., de Ferra F. Molecular mechanisms of action of interferon. Tex Rep Biol Med. 1981;41:471–478. [PubMed] [Google Scholar]
  3. Ball L. A. Induction, purification, and properties of 2'5' oligoadenylate synthetase. Ann N Y Acad Sci. 1980;350:486–496. doi: 10.1111/j.1749-6632.1980.tb20651.x. [DOI] [PubMed] [Google Scholar]
  4. Cayley P. J., Kerr I. M. Synthesis, characterisation and biological significance of (2'-5')oligoadenylate derivatives of NAD+, ADP-ribose and adenosine(5')tetraphospho(5')adenosine. Eur J Biochem. 1982 Mar 1;122(3):601–608. [PubMed] [Google Scholar]
  5. Etienne-Smekens M., Vassart G., Content J., Dumont J. E. Presence of 2'-5' A synthetase in dog liver. FEBS Lett. 1981 Mar 23;125(2):146–150. doi: 10.1016/0014-5793(81)80705-3. [DOI] [PubMed] [Google Scholar]
  6. Ferbus D., Justesen J., Besançon F., Thang M. N. The 2'5' oligoadenylate synthetase has a multifunctional 2'5' nucleotidyl-transferase activity. Biochem Biophys Res Commun. 1981 May 29;100(2):847–856. doi: 10.1016/s0006-291x(81)80251-3. [DOI] [PubMed] [Google Scholar]
  7. Frayssinet C., Gresser I., Tovey M., Lindahl P. Letter: Inhibitory effect of potent interferon preparations on the regeneration of mouse liver after partial hepatectomy. Nature. 1973 Sep 21;245(5421):146–147. doi: 10.1038/245146b0. [DOI] [PubMed] [Google Scholar]
  8. Hovanessian A. G., Kerr I. M. Synthesis of an oligonucleotide inhibitor of protein synthesis in rabbit reticulocyte lysates analogous to that formed in extracts from interferon-treated cells. Eur J Biochem. 1978 Mar;84(1):149–159. doi: 10.1111/j.1432-1033.1978.tb12151.x. [DOI] [PubMed] [Google Scholar]
  9. Hovanessian A. G., Wood J., Meurs E., Montagnier L. Increased nuclease activity in cells treated with pppA2'p5'A2'p5' A. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3261–3265. doi: 10.1073/pnas.76.7.3261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jutesen J., Ferbus D., Thang M. N. Properties of 2'5' oligoadenylate synthetase. Ann N Y Acad Sci. 1980;350:510–521. doi: 10.1111/j.1749-6632.1980.tb20653.x. [DOI] [PubMed] [Google Scholar]
  11. Kamiike W., Watanabe F., Hashimoto T., Tagawa K., Ikeda Y., Nakao K., Kawashima Y. Changes in cellular levels of ATP and its catabolites in ischemic rat liver. J Biochem. 1982 Apr;91(4):1349–1356. doi: 10.1093/oxfordjournals.jbchem.a133822. [DOI] [PubMed] [Google Scholar]
  12. Kerr I. M., Brown R. E. pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells. Proc Natl Acad Sci U S A. 1978 Jan;75(1):256–260. doi: 10.1073/pnas.75.1.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kimchi A. Increased levels of interferon-induced (2'--5') oligo-isoadenylate synthetase in mature T-lymphocytes and in differentiated Friend-erythroleukemic cells. J Interferon Res. 1981;1(4):559–569. doi: 10.1089/jir.1981.1.559. [DOI] [PubMed] [Google Scholar]
  14. Kimchi A., Shulman L., Schmidt A., Chernajovsky Y., Fradin A., Revel M. Kinetics of the induction of three translation-regulatory enzymes by interferon. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3208–3212. doi: 10.1073/pnas.76.7.3208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kimchi A., Shure H., Revel M. Anti-mitogenic function of interferon-induced (2'-5')oligo(adenylate) and growth-related variations in enzymes that synthesize and degrade this oligonucleotide. Eur J Biochem. 1981;114(1):5–10. doi: 10.1111/j.1432-1033.1981.tb06163.x. [DOI] [PubMed] [Google Scholar]
  16. Kimchi A., Shure H., Revel M. Regulation of lymphocyte mitogenesis by (2'--5') oligo-isoadenylate. Nature. 1979 Dec 20;282(5741):849–851. doi: 10.1038/282849a0. [DOI] [PubMed] [Google Scholar]
  17. Knight M., Cayley P. J., Silverman R. H., Wreschner D. H., Gilbert C. S., Brown R. E., Kerr I. M. Radioimmune, radiobinding and HPLC analysis of 2-5A and related oligonucleotides from intact cells. Nature. 1980 Nov 13;288(5787):189–192. doi: 10.1038/288189a0. [DOI] [PubMed] [Google Scholar]
  18. Krishnan I., Baglioni C. Elevated levels of (2'-5')oligoadenylic acid polymerase activity in growth-arrested human lymphoblastoid Namalva cells. Mol Cell Biol. 1981 Oct;1(10):932–938. doi: 10.1128/mcb.1.10.932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Krishnan I., Baglioni C. Increased levels of (2'-5')oligo(A) polymerase activity in human lymphoblastoid cells treated with glucocorticoids. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6506–6510. doi: 10.1073/pnas.77.11.6506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lebleu B., Content J. Mechanisms of interferon action: biochemical and genetic approaches. Interferon. 1982;4:47–94. [PubMed] [Google Scholar]
  21. Nilsen T. W., Maroney P. A., Baglioni C. Synthesis of (2'-5')oligoadenylate and activation of an endoribonuclease in interferon-treated HeLa cells infected with reovirus. J Virol. 1982 Jun;42(3):1039–1045. doi: 10.1128/jvi.42.3.1039-1045.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nilsen T. W., Maroney P. A., Robertson H. D., Baglioni C. Heterogeneous nuclear RNA promotes synthesis of (2',5')oligoadenylate and is cleaved by the (2',5')oligoadenylate-activated endoribonuclease. Mol Cell Biol. 1982 Feb;2(2):154–160. doi: 10.1128/mcb.2.2.154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nilsen T. W., Wood D. L., Baglioni C. 2',5'-Oligo(A)-activated endoribonuclease. Tissue distribution and characterization with a binding assay. J Biol Chem. 1981 Nov 10;256(21):10751–10754. [PubMed] [Google Scholar]
  24. Nilsen T. W., Wood D. L., Baglioni C. 2',5'-Oligo(A)-activated endoribonuclease. Tissue distribution and characterization with a binding assay. J Biol Chem. 1981 Nov 10;256(21):10751–10754. [PubMed] [Google Scholar]
  25. Nilsen T. W., Wood D. L., Baglioni C. Presence of 2',5'-oligo(A) and of enzymes that synthesize, bind, and degrade 2',5'-oligo(A) in HeLa cell nuclei. J Biol Chem. 1982 Feb 25;257(4):1602–1605. [PubMed] [Google Scholar]
  26. Oikarinen J. Cortisol induces (2'-5')oligoadenylate synthetase in cultured chick embryo tendon fibroblasts. Biochem Biophys Res Commun. 1982 Apr 14;105(3):876–881. doi: 10.1016/0006-291x(82)91051-8. [DOI] [PubMed] [Google Scholar]
  27. Samanta H., Dougherty J. P., Lengyel P. Synthesis of (2'-5')(A)n from ATP. Characteristics of the reaction catalyzed by (2'-5')(A)n synthetase purified from mouse Ehrlich ascites tumor cells treated with interferon. J Biol Chem. 1980 Oct 25;255(20):9807–9813. [PubMed] [Google Scholar]
  28. Schmidt A., Chernajovsky Y., Shulman L., Federman P., Berissi H., Revel M. An interferon-induced phosphodiesterase degrading (2'-5') oligoisoadenylate and the C-C-A terminus of tRNA. Proc Natl Acad Sci U S A. 1979 Oct;76(10):4788–4792. doi: 10.1073/pnas.76.10.4788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shimizu N., Sokawa Y. 2',5'-Oligoadenylate synthetase activity in lymphocytes from normal mouse. J Biol Chem. 1979 Dec 10;254(23):12034–12037. [PubMed] [Google Scholar]
  30. Silverman R. H., Cayley P. J., Knight M., Gilbert C. S., Kerr I. M. Control of the ppp(a2'p)nA system in HeLa cells. Effects of interferon and virus infection. Eur J Biochem. 1982 May;124(1):131–138. doi: 10.1111/j.1432-1033.1982.tb05915.x. [DOI] [PubMed] [Google Scholar]
  31. Smekens-Etienne M., Goldstein J., Ooms H. A., Dumont J. E. Variation of (2'-5')oligo(adenylate) synthetase activity during rat-liver regeneration. Eur J Biochem. 1983 Feb 1;130(2):269–273. doi: 10.1111/j.1432-1033.1983.tb07146.x. [DOI] [PubMed] [Google Scholar]
  32. Stark G. R., Dower W. J., Schimke R. T., Brown R. E., Kerr I. M. 2-5A synthetase: assay, distribution and variation with growth or hormone status. Nature. 1979 Mar 29;278(5703):471–473. doi: 10.1038/278471a0. [DOI] [PubMed] [Google Scholar]
  33. Vaquero C., Sancéau J., Falcoff R. Protein synthesis in extracts from interferon-treated Mengo virus infected cells. Biochem Biophys Res Commun. 1982 Aug;107(3):974–980. doi: 10.1016/0006-291x(82)90618-0. [DOI] [PubMed] [Google Scholar]
  34. Verhaegen-Lewalle M., Content J. 2'-Phosphodiesterase activity in human cell lines treated or untreated with human interferon. Eur J Biochem. 1982 Sep 1;126(3):639–643. doi: 10.1111/j.1432-1033.1982.tb06828.x. [DOI] [PubMed] [Google Scholar]
  35. Verhaegen M., Divizia M., Vandenbussche P., Kuwata T., Content J. Abnormal behavior of interferon-induced enzymatic activities in an interferon-resistant cell line. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4479–4483. doi: 10.1073/pnas.77.8.4479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Williams B. R., Golgher R. R., Brown R. E., Gilbert C. S., Kerr I. M. Natural occurrence of 2-5A in interferon-treated EMC virus-infected L cells. Nature. 1979 Dec 6;282(5739):582–586. doi: 10.1038/282582a0. [DOI] [PubMed] [Google Scholar]
  37. Williams B. R., Golgher R. R., Kerr I. M. Activation of a nuclease by pppA2'p5'A2'p5'A in intact cells. FEBS Lett. 1979 Sep 1;105(1):47–52. doi: 10.1016/0014-5793(79)80885-6. [DOI] [PubMed] [Google Scholar]
  38. Wreschner D. H., Silverman R. H., James T. C., Gilbert C. S., Kerr I. M. Affinity labelling and characterization of the ppp(A2'p)nA-dependent endoribonuclease from different mammalian sources. Eur J Biochem. 1982 May 17;124(2):261–268. doi: 10.1111/j.1432-1033.1982.tb06586.x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES