Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1996 Apr 15;15(8):1753–1765.

Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants.

M Buck 1, M Chojkier 1
PMCID: PMC450091  PMID: 8617220

Abstract

Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor alpha (TNF alpha) induces oxidative stress and nitric oxide synthase (NOS) in skeletal muscle, leading to decreased myosin creatinine phosphokinase (MCK) expression and binding activities. The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein. Treatment of skeletal muscle cells with a phorbol ester, a superoxide-generating system, an NO donor or a Jun-D antisense oligonucleotide decreased Jun-D activity and transcription from the MCK-E box, which were prevented by antioxidants, a scavenger of reducing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNF alpha mice with the antioxidants D-alpha-tocopherol of BW755c, or the NOS inhibitor nitro-L-arginine.

Full text

PDF
1754

Images in this article

1754Image
on p.1754
1755Image
on p.1755
1757Image
on p.1757
1758Image
on p.1758
1758Image
on p.1758
1759Image
on p.1759
1760Image
on p.1760

Selected References

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

  1. Abate C., Patel L., Rauscher F. J., 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science. 1990 Sep 7;249(4973):1157–1161. doi: 10.1126/science.2118682. [DOI] [PubMed] [Google Scholar]
  2. Akira S., Hirano T., Taga T., Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990 Aug;4(11):2860–2867. [PubMed] [Google Scholar]
  3. Bengal E., Ransone L., Scharfmann R., Dwarki V. J., Tapscott S. J., Weintraub H., Verma I. M. Functional antagonism between c-Jun and MyoD proteins: a direct physical association. Cell. 1992 Feb 7;68(3):507–519. doi: 10.1016/0092-8674(92)90187-h. [DOI] [PubMed] [Google Scholar]
  4. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  5. Brennan T. J., Olson E. N. Myogenin resides in the nucleus and acquires high affinity for a conserved enhancer element on heterodimerization. Genes Dev. 1990 Apr;4(4):582–595. doi: 10.1101/gad.4.4.582. [DOI] [PubMed] [Google Scholar]
  6. Brenner D. A., Buck M., Feitelberg S. P., Chojkier M. Tumor necrosis factor-alpha inhibits albumin gene expression in a murine model of cachexia. J Clin Invest. 1990 Jan;85(1):248–255. doi: 10.1172/JCI114419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brenner D. A., Chojkier M. Acetaldehyde increases collagen gene transcription in cultured human fibroblasts. J Biol Chem. 1987 Dec 25;262(36):17690–17695. [PubMed] [Google Scholar]
  8. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  9. Buck M., Turler H., Chojkier M. LAP (NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation. EMBO J. 1994 Feb 15;13(4):851–860. doi: 10.1002/j.1460-2075.1994.tb06328.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chaudhary A. K., Nokubo M., Reddy G. R., Yeola S. N., Morrow J. D., Blair I. A., Marnett L. J. Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver. Science. 1994 Sep 9;265(5178):1580–1582. doi: 10.1126/science.8079172. [DOI] [PubMed] [Google Scholar]
  11. Cheng J., Turksen K., Yu Q. C., Schreiber H., Teng M., Fuchs E. Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice. Genes Dev. 1992 Aug;6(8):1444–1456. doi: 10.1101/gad.6.8.1444. [DOI] [PubMed] [Google Scholar]
  12. Chojkier M., Houglum K., Solis-Herruzo J., Brenner D. A. Stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts. A role for lipid peroxidation? J Biol Chem. 1989 Oct 5;264(28):16957–16962. [PubMed] [Google Scholar]
  13. Costelli P., Carbó N., Tessitore L., Bagby G. J., Lopez-Soriano F. J., Argilés J. M., Baccino F. M. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest. 1993 Dec;92(6):2783–2789. doi: 10.1172/JCI116897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Descombes P., Chojkier M., Lichtsteiner S., Falvey E., Schibler U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 1990 Sep;4(9):1541–1551. doi: 10.1101/gad.4.9.1541. [DOI] [PubMed] [Google Scholar]
  15. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Flores E. A., Bistrian B. R., Pomposelli J. J., Dinarello C. A., Blackburn G. L., Istfan N. W. Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J Clin Invest. 1989 May;83(5):1614–1622. doi: 10.1172/JCI114059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fong Y., Moldawer L. L., Marano M., Wei H., Barber A., Manogue K., Tracey K. J., Kuo G., Fischman D. A., Cerami A. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol. 1989 Mar;256(3 Pt 2):R659–R665. doi: 10.1152/ajpregu.1989.256.3.R659. [DOI] [PubMed] [Google Scholar]
  18. Goodman J. C., Robertson C. S., Grossman R. G., Narayan R. K. Elevation of tumor necrosis factor in head injury. J Neuroimmunol. 1990 Dec;30(2-3):213–217. doi: 10.1016/0165-5728(90)90105-v. [DOI] [PubMed] [Google Scholar]
  19. Grau G. E., Taylor T. E., Molyneux M. E., Wirima J. J., Vassalli P., Hommel M., Lambert P. H. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med. 1989 Jun 15;320(24):1586–1591. doi: 10.1056/NEJM198906153202404. [DOI] [PubMed] [Google Scholar]
  20. Hasty P., Bradley A., Morris J. H., Edmondson D. G., Venuti J. M., Olson E. N., Klein W. H. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature. 1993 Aug 5;364(6437):501–506. doi: 10.1038/364501a0. [DOI] [PubMed] [Google Scholar]
  21. Henkel T., Machleidt T., Alkalay I., Krönke M., Ben-Neriah Y., Baeuerle P. A. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature. 1993 Sep 9;365(6442):182–185. doi: 10.1038/365182a0. [DOI] [PubMed] [Google Scholar]
  22. Holvoet P., Perez G., Zhao Z., Brouwers E., Bernar H., Collen D. Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease. J Clin Invest. 1995 Jun;95(6):2611–2619. doi: 10.1172/JCI117963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Houglum K., Brenner D. A., Chojkier M. d-alpha-tocopherol inhibits collagen alpha 1(I) gene expression in cultured human fibroblasts. Modulation of constitutive collagen gene expression by lipid peroxidation. J Clin Invest. 1991 Jun;87(6):2230–2235. doi: 10.1172/JCI115258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Houglum K., Filip M., Witztum J. L., Chojkier M. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload. J Clin Invest. 1990 Dec;86(6):1991–1998. doi: 10.1172/JCI114934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kaushal S., Schneider J. W., Nadal-Ginard B., Mahdavi V. Activation of the myogenic lineage by MEF2A, a factor that induces and cooperates with MyoD. Science. 1994 Nov 18;266(5188):1236–1240. doi: 10.1126/science.7973707. [DOI] [PubMed] [Google Scholar]
  26. Kilbourn R. G., Gross S. S., Jubran A., Adams J., Griffith O. W., Levi R., Lodato R. F. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A. 1990 May;87(9):3629–3632. doi: 10.1073/pnas.87.9.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kobzik L., Reid M. B., Bredt D. S., Stamler J. S. Nitric oxide in skeletal muscle. Nature. 1994 Dec 8;372(6506):546–548. doi: 10.1038/372546a0. [DOI] [PubMed] [Google Scholar]
  28. Lassar A. B., Buskin J. N., Lockshon D., Davis R. L., Apone S., Hauschka S. D., Weintraub H. MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to the muscle creatine kinase enhancer. Cell. 1989 Sep 8;58(5):823–831. doi: 10.1016/0092-8674(89)90935-5. [DOI] [PubMed] [Google Scholar]
  29. Li L., Chambard J. C., Karin M., Olson E. N. Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression. Genes Dev. 1992 Apr;6(4):676–689. doi: 10.1101/gad.6.4.676. [DOI] [PubMed] [Google Scholar]
  30. Li L., Hu J. S., Olson E. N. Different members of the jun proto-oncogene family exhibit distinct patterns of expression in response to type beta transforming growth factor. J Biol Chem. 1990 Jan 25;265(3):1556–1562. [PubMed] [Google Scholar]
  31. Li L., Zhou J., James G., Heller-Harrison R., Czech M. P., Olson E. N. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. Cell. 1992 Dec 24;71(7):1181–1194. doi: 10.1016/s0092-8674(05)80066-2. [DOI] [PubMed] [Google Scholar]
  32. Lipton S. A., Choi Y. B., Pan Z. H., Lei S. Z., Chen H. S., Sucher N. J., Loscalzo J., Singel D. J., Stamler J. S. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626–632. doi: 10.1038/364626a0. [DOI] [PubMed] [Google Scholar]
  33. McWhirter R. B., Hille R. The reductive half-reaction of xanthine oxidase. Identification of spectral intermediates in the hydroxylation of 2-hydroxy-6-methylpurine. J Biol Chem. 1991 Dec 15;266(35):23724–23731. [PubMed] [Google Scholar]
  34. Meier B., Radeke H. H., Selle S., Younes M., Sies H., Resch K., Habermehl G. G. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J. 1989 Oct 15;263(2):539–545. doi: 10.1042/bj2630539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Moldawer L. L., Svaninger G., Gelin J., Lundholm K. G. Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol. 1987 Dec;253(6 Pt 1):C766–C773. doi: 10.1152/ajpcell.1987.253.6.C766. [DOI] [PubMed] [Google Scholar]
  36. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  37. Nabeshima Y., Hanaoka K., Hayasaka M., Esumi E., Li S., Nonaka I., Nabeshima Y. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature. 1993 Aug 5;364(6437):532–535. doi: 10.1038/364532a0. [DOI] [PubMed] [Google Scholar]
  38. Nakabeppu Y., Ryder K., Nathans D. DNA binding activities of three murine Jun proteins: stimulation by Fos. Cell. 1988 Dec 2;55(5):907–915. doi: 10.1016/0092-8674(88)90146-8. [DOI] [PubMed] [Google Scholar]
  39. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  40. Palombella V. J., Rando O. J., Goldberg A. L., Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. doi: 10.1016/s0092-8674(94)90482-0. [DOI] [PubMed] [Google Scholar]
  41. Pfarr C. M., Mechta F., Spyrou G., Lallemand D., Carillo S., Yaniv M. Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell. 1994 Feb 25;76(4):747–760. doi: 10.1016/0092-8674(94)90513-4. [DOI] [PubMed] [Google Scholar]
  42. Roubenoff R., Roubenoff R. A., Cannon J. G., Kehayias J. J., Zhuang H., Dawson-Hughes B., Dinarello C. A., Rosenberg I. H. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994 Jun;93(6):2379–2386. doi: 10.1172/JCI117244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ryseck R. P., Bravo R. c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene. 1991 Apr;6(4):533–542. [PubMed] [Google Scholar]
  44. Sassoon D., Lyons G., Wright W. E., Lin V., Lassar A., Weintraub H., Buckingham M. Expression of two myogenic regulatory factors myogenin and MyoD1 during mouse embryogenesis. Nature. 1989 Sep 28;341(6240):303–307. doi: 10.1038/341303a0. [DOI] [PubMed] [Google Scholar]
  45. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schulze-Osthoff K., Beyaert R., Vandevoorde V., Haegeman G., Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 1993 Aug;12(8):3095–3104. doi: 10.1002/j.1460-2075.1993.tb05978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Scuderi P., Sterling K. E., Lam K. S., Finley P. R., Ryan K. J., Ray C. G., Petersen E., Slymen D. J., Salmon S. E. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet. 1986 Dec 13;2(8520):1364–1365. doi: 10.1016/s0140-6736(86)92007-6. [DOI] [PubMed] [Google Scholar]
  48. Sherry B. A., Gelin J., Fong Y., Marano M., Wei H., Cerami A., Lowry S. F., Lundholm K. G., Moldawer L. L. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J. 1989 Jun;3(8):1956–1962. doi: 10.1096/fasebj.3.8.2721856. [DOI] [PubMed] [Google Scholar]
  49. Skapek S. X., Rhee J., Spicer D. B., Lassar A. B. Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase. Science. 1995 Feb 17;267(5200):1022–1024. doi: 10.1126/science.7863328. [DOI] [PubMed] [Google Scholar]
  50. Spiegelman B. M., Hotamisligil G. S. Through thick and thin: wasting, obesity, and TNF alpha. Cell. 1993 May 21;73(4):625–627. doi: 10.1016/0092-8674(93)90243-j. [DOI] [PubMed] [Google Scholar]
  51. Stamler J. S. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994 Sep 23;78(6):931–936. doi: 10.1016/0092-8674(94)90269-0. [DOI] [PubMed] [Google Scholar]
  52. Starnes H. F., Jr, Warren R. S., Jeevanandam M., Gabrilove J. L., Larchian W., Oettgen H. F., Brennan M. F. Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest. 1988 Oct;82(4):1321–1325. doi: 10.1172/JCI113733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Strassmann G., Fong M., Kenney J. S., Jacob C. O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest. 1992 May;89(5):1681–1684. doi: 10.1172/JCI115767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tapscott S. J., Thayer M. J., Weintraub H. Deficiency in rhabdomyosarcomas of a factor required for MyoD activity and myogenesis. Science. 1993 Mar 5;259(5100):1450–1453. doi: 10.1126/science.8383879. [DOI] [PubMed] [Google Scholar]
  55. Tracey K. J., Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol. 1993;9:317–343. doi: 10.1146/annurev.cb.09.110193.001533. [DOI] [PubMed] [Google Scholar]
  56. Tracey K. J., Morgello S., Koplin B., Fahey T. J., 3rd, Fox J., Aledo A., Manogue K. R., Cerami A. Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia. J Clin Invest. 1990 Dec;86(6):2014–2024. doi: 10.1172/JCI114937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tracey K. J., Wei H., Manogue K. R., Fong Y., Hesse D. G., Nguyen H. T., Kuo G. C., Beutler B., Cotran R. S., Cerami A. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988 Mar 1;167(3):1211–1227. doi: 10.1084/jem.167.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Traenckner E. B., Wilk S., Baeuerle P. A. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J. 1994 Nov 15;13(22):5433–5441. doi: 10.1002/j.1460-2075.1994.tb06878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Trautwein C., Caelles C., van der Geer P., Hunter T., Karin M., Chojkier M. Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature. 1993 Aug 5;364(6437):544–547. doi: 10.1038/364544a0. [DOI] [PubMed] [Google Scholar]
  60. Trautwein C., van der Geer P., Karin M., Hunter T., Chojkier M. Protein kinase A and C site-specific phosphorylations of LAP (NF-IL6) modulate its binding affinity to DNA recognition elements. J Clin Invest. 1994 Jun;93(6):2554–2561. doi: 10.1172/JCI117266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Vale R. D. Getting a grip on myosin. Cell. 1994 Sep 9;78(5):733–737. doi: 10.1016/s0092-8674(94)90402-2. [DOI] [PubMed] [Google Scholar]
  62. Voth R., Rossol S., Klein K., Hess G., Schütt K. H., Schröder H. C., Meyer zum Büschenfelde K. H., Müller W. E. Differential gene expression of IFN-alpha and tumor necrosis factor-alpha in peripheral blood mononuclear cells from patients with AIDS related complex and AIDS. J Immunol. 1990 Feb 1;144(3):970–975. [PubMed] [Google Scholar]
  63. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  64. Weintraub H., Davis R., Lockshon D., Lassar A. MyoD binds cooperatively to two sites in a target enhancer sequence: occupancy of two sites is required for activation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5623–5627. doi: 10.1073/pnas.87.15.5623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wing S. S., Goldberg A. L. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting. Am J Physiol. 1993 Apr;264(4 Pt 1):E668–E676. doi: 10.1152/ajpendo.1993.264.4.E668. [DOI] [PubMed] [Google Scholar]
  66. Wong G. H., Elwell J. H., Oberley L. W., Goeddel D. V. Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell. 1989 Sep 8;58(5):923–931. doi: 10.1016/0092-8674(89)90944-6. [DOI] [PubMed] [Google Scholar]
  67. Xanthoudakis S., Curran T. Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity. EMBO J. 1992 Feb;11(2):653–665. doi: 10.1002/j.1460-2075.1992.tb05097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Xanthoudakis S., Miao G., Wang F., Pan Y. C., Curran T. Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. EMBO J. 1992 Sep;11(9):3323–3335. doi: 10.1002/j.1460-2075.1992.tb05411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Yoneda T., Alsina M. A., Chavez J. B., Bonewald L., Nishimura R., Mundy G. R. Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice. J Clin Invest. 1991 Mar;87(3):977–985. doi: 10.1172/JCI115106. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES