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. 1991 May;10(5):1119–1125. doi: 10.1002/j.1460-2075.1991.tb08052.x

N-myc disrupts protein kinase C-mediated signal transduction in neuroblastoma.

R Bernards 1
PMCID: PMC452765  PMID: 1902412

Abstract

In neuroblastoma, amplification of the N-myc gene is closely correlated with increased metastatic ability. The mechanism by which N-myc acts to increase neuroblastoma malignancy is poorly understood as yet. It is shown here that transfection of N-myc in a neuroblastoma cell line causes suppression of one isoform of protein kinase C, named delta, and induction of an unusual type of protein kinase C, named zeta. N-myc-transfected neuroblastoma cells were found to be blocked in the activation of both c-fos mRNA and the NF-kappa B transcription factor by phorbol ester. Introduction of a protein kinase C expression vector in N-myc transfected neuroblastoma cells restored inducibility of both c-fos and NF-kappa B by phorbol ester. These observations indicate that changes in protein kinase C gene expression significantly alter the response of N-myc-amplified neuroblastomas to a variety of external signals.

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Selected References

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  1. Akeson R., Bernards R. N-myc down regulates neural cell adhesion molecule expression in rat neuroblastoma. Mol Cell Biol. 1990 May;10(5):2012–2016. doi: 10.1128/mcb.10.5.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baeuerle P. A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell. 1988 Apr 22;53(2):211–217. doi: 10.1016/0092-8674(88)90382-0. [DOI] [PubMed] [Google Scholar]
  3. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  4. Baldwin A. S., Jr, Sharp P. A. Two transcription factors, NF-kappa B and H2TF1, interact with a single regulatory sequence in the class I major histocompatibility complex promoter. Proc Natl Acad Sci U S A. 1988 Feb;85(3):723–727. doi: 10.1073/pnas.85.3.723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ballard D. W., Walker W. H., Doerre S., Sista P., Molitor J. A., Dixon E. P., Peffer N. J., Hannink M., Greene W. C. The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function. Cell. 1990 Nov 16;63(4):803–814. doi: 10.1016/0092-8674(90)90146-6. [DOI] [PubMed] [Google Scholar]
  6. Bernards R., Dessain S. K., Weinberg R. A. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell. 1986 Dec 5;47(5):667–674. doi: 10.1016/0092-8674(86)90509-x. [DOI] [PubMed] [Google Scholar]
  7. Bollag G. E., Roth R. A., Beaudoin J., Mochly-Rosen D., Koshland D. E., Jr Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5822–5824. doi: 10.1073/pnas.83.16.5822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borner C., Guadagno S. N., Hsieh L. L., Hsiao W. L., Weinstein I. B. Transformation by a ras oncogene causes increased expression of protein kinase C-alpha and decreased expression of protein kinase C-epsilon. Cell Growth Differ. 1990 Dec;1(12):653–660. [PubMed] [Google Scholar]
  9. Brodeur G. M., Seeger R. C., Schwab M., Varmus H. E., Bishop J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984 Jun 8;224(4653):1121–1124. doi: 10.1126/science.6719137. [DOI] [PubMed] [Google Scholar]
  10. Choi P. M., Tchou-Wong K. M., Weinstein I. B. Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression. Mol Cell Biol. 1990 Sep;10(9):4650–4657. doi: 10.1128/mcb.10.9.4650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fisch T. M., Prywes R., Roeder R. G. c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore. Mol Cell Biol. 1987 Oct;7(10):3490–3502. doi: 10.1128/mcb.7.10.3490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gandino L., Di Renzo M. F., Giordano S., Bussolino F., Comoglio P. M. Protein kinase-c activation inhibits tyrosine phosphorylation of the c-met protein. Oncogene. 1990 May;5(5):721–725. [PubMed] [Google Scholar]
  14. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  15. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gould K. L., Woodgett J. R., Cooper J. A., Buss J. E., Shalloway D., Hunter T. Protein kinase C phosphorylates pp60src at a novel site. Cell. 1985 Oct;42(3):849–857. doi: 10.1016/0092-8674(85)90281-8. [DOI] [PubMed] [Google Scholar]
  17. Hall C. V., Jacob P. E., Ringold G. M., Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed] [Google Scholar]
  18. Housey G. M., Johnson M. D., Hsiao W. L., O'Brian C. A., Murphy J. P., Kirschmeier P., Weinstein I. B. Overproduction of protein kinase C causes disordered growth control in rat fibroblasts. Cell. 1988 Feb 12;52(3):343–354. doi: 10.1016/s0092-8674(88)80027-8. [DOI] [PubMed] [Google Scholar]
  19. Hunter T., Ling N., Cooper J. A. Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. Nature. 1984 Oct 4;311(5985):480–483. doi: 10.1038/311480a0. [DOI] [PubMed] [Google Scholar]
  20. Jones N. Transcriptional regulation by dimerization: two sides to an incestuous relationship. Cell. 1990 Apr 6;61(1):9–11. doi: 10.1016/0092-8674(90)90207-u. [DOI] [PubMed] [Google Scholar]
  21. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  22. Lenardo M., Rustgi A. K., Schievella A. R., Bernards R. Suppression of MHC class I gene expression by N-myc through enhancer inactivation. EMBO J. 1989 Nov;8(11):3351–3355. doi: 10.1002/j.1460-2075.1989.tb08497.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lin C. R., Chen W. S., Lazar C. S., Carpenter C. D., Gill G. N., Evans R. M., Rosenfeld M. G. Protein kinase C phosphorylation at Thr 654 of the unoccupied EGF receptor and EGF binding regulate functional receptor loss by independent mechanisms. Cell. 1986 Mar 28;44(6):839–848. doi: 10.1016/0092-8674(86)90006-1. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  26. Ono Y., Fujii T., Ogita K., Kikkawa U., Igarashi K., Nishizuka Y. Protein kinase C zeta subspecies from rat brain: its structure, expression, and properties. Proc Natl Acad Sci U S A. 1989 May;86(9):3099–3103. doi: 10.1073/pnas.86.9.3099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ono Y., Fujii T., Ogita K., Kikkawa U., Igarashi K., Nishizuka Y. The structure, expression, and properties of additional members of the protein kinase C family. J Biol Chem. 1988 May 15;263(14):6927–6932. [PubMed] [Google Scholar]
  28. Pierce J. W., Lenardo M., Baltimore D. Oligonucleotide that binds nuclear factor NF-kappa B acts as a lymphoid-specific and inducible enhancer element. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1482–1486. doi: 10.1073/pnas.85.5.1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Prywes R., Roeder R. G. Inducible binding of a factor to the c-fos enhancer. Cell. 1986 Dec 5;47(5):777–784. doi: 10.1016/0092-8674(86)90520-9. [DOI] [PubMed] [Google Scholar]
  30. Påhlman S., Odelstad L., Larsson E., Grotte G., Nilsson K. Phenotypic changes of human neuroblastoma cells in culture induced by 12-O-tetradecanoyl-phorbol-13-acetate. Int J Cancer. 1981 Nov 15;28(5):583–589. doi: 10.1002/ijc.2910280509. [DOI] [PubMed] [Google Scholar]
  31. Ramsay G., Stanton L., Schwab M., Bishop J. M. Human proto-oncogene N-myc encodes nuclear proteins that bind DNA. Mol Cell Biol. 1986 Dec;6(12):4450–4457. doi: 10.1128/mcb.6.12.4450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Seeger R. C., Brodeur G. M., Sather H., Dalton A., Siegel S. E., Wong K. Y., Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985 Oct 31;313(18):1111–1116. doi: 10.1056/NEJM198510313131802. [DOI] [PubMed] [Google Scholar]
  33. Sen R., Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. doi: 10.1016/0092-8674(86)90807-x. [DOI] [PubMed] [Google Scholar]
  34. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]
  35. Zimmerman K. A., Yancopoulos G. D., Collum R. G., Smith R. K., Kohl N. E., Denis K. A., Nau M. M., Witte O. N., Toran-Allerand D., Gee C. E. Differential expression of myc family genes during murine development. 1986 Feb 27-Mar 5Nature. 319(6056):780–783. doi: 10.1038/319780a0. [DOI] [PubMed] [Google Scholar]
  36. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

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