Skip to main content
NCBI 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
. 1991 Mar 15;88(6):2156–2160. doi: 10.1073/pnas.88.6.2156

Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN.

D E Hallahan 1, V P Sukhatme 1, M L Sherman 1, S Virudachalam 1, D Kufe 1, R R Weichselbaum 1
PMCID: PMC51188  PMID: 1900938

Abstract

The cellular response to ionizing radiation includes growth arrest and DNA repair followed by proliferation. Induction of immediate early response genes may participate in signal transduction preceding these phenotypic responses. We analyzed mRNA expression for different classes of immediate early genes (JUN, EGR1, and FOS) after cellular x-irradiation. Increased expression of the EGR1 and JUN genes was observed within 0.5-3 hr following x-ray exposure. Preincubation with cycloheximide was associated with superinduction of JUN and EGR1 in x-irradiated cells. Inhibition of protein kinase C activity by prolonged stimulation with phorbol 12-myristate 13-acetate or the protein kinase inhibitor H7 prior to irradiation attenuated the increase in EGR1 and JUN transcripts. FOS expression was not coregulated with that of EGR1 following x-irradiation, suggesting a distinct regulatory pathway of this gene as compared with its regulation following serum and phorbol ester. These data implicate the EGR1 and JUN proteins as signal transducers during the cellular response to radiation injury and suggest that this effect is mediated in part by a protein kinase C-dependent pathway.

Full text

PDF
2156

Images in this article

2157Image
on p.2157
2157Image
on p.2157
2157Image
on p.2157
2157Image
on p.2157
2158Image
on p.2158
2158Image
on p.2158
2158Image
on p.2158
2158Image
on p.2158
2158Image
on p.2158

Selected References

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

  1. Asano T., Hidaka H. Vasodilatory action of HA1004 [N-(2-guanidinoethyl)-5-isoquinolinesulfonamide], a novel calcium antagonist with no effect on cardiac function. J Pharmacol Exp Ther. 1984 Oct;231(1):141–145. [PubMed] [Google Scholar]
  2. Cao X. M., Koski R. A., Gashler A., McKiernan M., Morris C. F., Gaffney R., Hay R. V., Sukhatme V. P. Identification and characterization of the Egr-1 gene product, a DNA-binding zinc finger protein induced by differentiation and growth signals. Mol Cell Biol. 1990 May;10(5):1931–1939. doi: 10.1128/mcb.10.5.1931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chavrier P., Zerial M., Lemaire P., Almendral J., Bravo R., Charnay P. A gene encoding a protein with zinc fingers is activated during G0/G1 transition in cultured cells. EMBO J. 1988 Jan;7(1):29–35. doi: 10.1002/j.1460-2075.1988.tb02780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Christy B. A., Lau L. F., Nathans D. A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7857–7861. doi: 10.1073/pnas.85.21.7857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Christy B., Nathans D. DNA binding site of the growth factor-inducible protein Zif268. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8737–8741. doi: 10.1073/pnas.86.22.8737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen D. R., Curran T. fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Mol Cell Biol. 1988 May;8(5):2063–2069. doi: 10.1128/mcb.8.5.2063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cole G. M., Schild D., Lovett S. T., Mortimer R. K. Regulation of RAD54- and RAD52-lacZ gene fusions in Saccharomyces cerevisiae in response to DNA damage. Mol Cell Biol. 1987 Mar;7(3):1078–1084. doi: 10.1128/mcb.7.3.1078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curran T., Franza B. R., Jr Fos and Jun: the AP-1 connection. Cell. 1988 Nov 4;55(3):395–397. doi: 10.1016/0092-8674(88)90024-4. [DOI] [PubMed] [Google Scholar]
  10. Curran T., Gordon M. B., Rubino K. L., Sambucetti L. C. Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro. Oncogene. 1987;2(1):79–84. [PubMed] [Google Scholar]
  11. Economou J. S., Rhoades K., Essner R., McBride W. H., Gasson J. C., Morton D. L. Genetic analysis of the human tumor necrosis factor alpha/cachectin promoter region in a macrophage cell line. J Exp Med. 1989 Jul 1;170(1):321–326. doi: 10.1084/jem.170.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fornace A. J., Jr, Alamo I., Jr, Hollander M. C. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8800–8804. doi: 10.1073/pnas.85.23.8800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fornace A. J., Jr, Nebert D. W., Hollander M. C., Luethy J. D., Papathanasiou M., Fargnoli J., Holbrook N. J. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989 Oct;9(10):4196–4203. doi: 10.1128/mcb.9.10.4196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  15. Gius D., Cao X. M., Rauscher F. J., 3rd, Cohen D. R., Curran T., Sukhatme V. P. Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements. Mol Cell Biol. 1990 Aug;10(8):4243–4255. doi: 10.1128/mcb.10.8.4243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hallahan D. E., Spriggs D. R., Beckett M. A., Kufe D. W., Weichselbaum R. R. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10104–10107. doi: 10.1073/pnas.86.24.10104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hattori K., Angel P., Le Beau M. M., Karin M. Structure and chromosomal localization of the functional intronless human JUN protooncogene. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9148–9152. doi: 10.1073/pnas.85.23.9148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hermens A. F., Barendsen G. W. Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after x-irradiation. Eur J Cancer. 1969 May;5(2):173–189. doi: 10.1016/0014-2964(69)90065-6. [DOI] [PubMed] [Google Scholar]
  19. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  20. Jamieson G. A., Jr, Mayforth R. D., Villereal M. L., Sukhatme V. P. Multiple intracellular pathways induce expression of a zinc-finger encoding gene (EGR1): relationship to activation of the Na/H exchanger. J Cell Physiol. 1989 May;139(2):262–268. doi: 10.1002/jcp.1041390207. [DOI] [PubMed] [Google Scholar]
  21. Joseph L. J., Le Beau M. M., Jamieson G. A., Jr, Acharya S., Shows T. B., Rowley J. D., Sukhatme V. P. Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7164–7168. doi: 10.1073/pnas.85.19.7164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kikkawa U., Kishimoto A., Nishizuka Y. The protein kinase C family: heterogeneity and its implications. Annu Rev Biochem. 1989;58:31–44. doi: 10.1146/annurev.bi.58.070189.000335. [DOI] [PubMed] [Google Scholar]
  23. Lamph W. W., Wamsley P., Sassone-Corsi P., Verma I. M. Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988 Aug 18;334(6183):629–631. doi: 10.1038/334629a0. [DOI] [PubMed] [Google Scholar]
  24. Lemaire P., Revelant O., Bravo R., Charnay P. Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4691–4695. doi: 10.1073/pnas.85.13.4691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lim R. W., Varnum B. C., Herschman H. R. Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene. 1987;1(3):263–270. [PubMed] [Google Scholar]
  26. Lin C. S., Goldthwait D. A., Samols D. Induction of transcription from the long terminal repeat of Moloney murine sarcoma provirus by UV-irradiation, x-irradiation, and phorbol ester. Proc Natl Acad Sci U S A. 1990 Jan;87(1):36–40. doi: 10.1073/pnas.87.1.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Little J. W., Mount D. W. The SOS regulatory system of Escherichia coli. Cell. 1982 May;29(1):11–22. doi: 10.1016/0092-8674(82)90085-x. [DOI] [PubMed] [Google Scholar]
  28. Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987 Nov 6;238(4828):797–799. doi: 10.1126/science.3672127. [DOI] [PubMed] [Google Scholar]
  29. Nishina H., Sato H., Suzuki T., Sato M., Iba H. Isolation and characterization of fra-2, an additional member of the fos gene family. Proc Natl Acad Sci U S A. 1990 May;87(9):3619–3623. doi: 10.1073/pnas.87.9.3619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ouellette A. J., Malt R. A., Sukhatme V. P., Bonventre J. V. Expression of two "immediate early" genes, Egr-1 and c-fos, in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest. 1990 Mar;85(3):766–771. doi: 10.1172/JCI114502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rorsman F., Bywater M., Knott T. J., Scott J., Betsholtz C. Structural characterization of the human platelet-derived growth factor A-chain cDNA and gene: alternative exon usage predicts two different precursor proteins. Mol Cell Biol. 1988 Feb;8(2):571–577. doi: 10.1128/mcb.8.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ryder K., Lanahan A., Perez-Albuerne E., Nathans D. jun-D: a third member of the jun gene family. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1500–1503. doi: 10.1073/pnas.86.5.1500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ryder K., Lau L. F., Nathans D. A gene activated by growth factors is related to the oncogene v-jun. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1487–1491. doi: 10.1073/pnas.85.5.1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ryder K., Nathans D. Induction of protooncogene c-jun by serum growth factors. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8464–8467. doi: 10.1073/pnas.85.22.8464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ryseck R. P., Hirai S. I., Yaniv M., Bravo R. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature. 1988 Aug 11;334(6182):535–537. doi: 10.1038/334535a0. [DOI] [PubMed] [Google Scholar]
  36. Sherman M. L., Datta R., Hallahan D. E., Weichselbaum R. R., Kufe D. W. Ionizing radiation regulates expression of the c-jun protooncogene. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5663–5666. doi: 10.1073/pnas.87.15.5663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sukhatme V. P., Cao X. M., Chang L. C., Tsai-Morris C. H., Stamenkovich D., Ferreira P. C., Cohen D. R., Edwards S. A., Shows T. B., Curran T. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988 Apr 8;53(1):37–43. doi: 10.1016/0092-8674(88)90485-0. [DOI] [PubMed] [Google Scholar]
  38. Sukhatme V. P. Early transcriptional events in cell growth: the Egr family. J Am Soc Nephrol. 1990 Dec;1(6):859–866. doi: 10.1681/ASN.V16859. [DOI] [PubMed] [Google Scholar]
  39. Sukhatme V. P., Kartha S., Toback F. G., Taub R., Hoover R. G., Tsai-Morris C. H. A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. Oncogene Res. 1987 Sep-Oct;1(4):343–355. [PubMed] [Google Scholar]
  40. Tsai-Morris C. H., Cao X. M., Sukhatme V. P. 5' flanking sequence and genomic structure of Egr-1, a murine mitogen inducible zinc finger encoding gene. Nucleic Acids Res. 1988 Sep 26;16(18):8835–8846. doi: 10.1093/nar/16.18.8835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tubiana M. Repopulation in human tumors. A biological background for fractionation in radiotherapy. Acta Oncol. 1988;27(2):83–88. doi: 10.3109/02841868809090328. [DOI] [PubMed] [Google Scholar]
  42. Weichselbaum R. R., Dahlberg W., Beckett M., Karrison T., Miller D., Clark J., Ervin T. J. Radiation-resistant and repair-proficient human tumor cells may be associated with radiotherapy failure in head- and neck-cancer patients. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2684–2688. doi: 10.1073/pnas.83.8.2684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weinstein I. B. The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment--twenty-seventh G.H.A. Clowes memorial award lecture. Cancer Res. 1988 Aug 1;48(15):4135–4143. [PubMed] [Google Scholar]
  44. Witte L., Fuks Z., Haimovitz-Friedman A., Vlodavsky I., Goodman D. S., Eldor A. Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells. Cancer Res. 1989 Sep 15;49(18):5066–5072. [PubMed] [Google Scholar]
  45. Zerial M., Toschi L., Ryseck R. P., Schuermann M., Müller R., Bravo R. The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. EMBO J. 1989 Mar;8(3):805–813. doi: 10.1002/j.1460-2075.1989.tb03441.x. [DOI] [PMC free article] [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