Skip to main content
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
. 1993 Aug 1;90(15):6944–6948. doi: 10.1073/pnas.90.15.6944

Interferon alpha induces protein kinase C-epsilon (PKC-epsilon) gene expression and a 4.7-kb PKC-epsilon-related transcript.

C Wang 1, S N Constantinescu 1, D J MacEwan 1, B Strulovici 1, L V Dekker 1, P J Parker 1, L M Pfeffer 1
PMCID: PMC47051  PMID: 8346200

Abstract

Protein kinases play key roles in the induction by human interferon alpha (IFN-alpha) of specific gene expression and biological activity in various human cell lines. We now report that IFN-alpha increased the 7-kb transcript for the epsilon isotype of protein kinase C (PKC-epsilon) and the cellular content of PKC-epsilon 24 and 48 hr after IFN-alpha addition (a 2-fold and 6-fold increase, respectively). Furthermore, IFN-alpha markedly induced a 4.7-kb transcript that hybridized to a PKC-epsilon-specific, but not to a PKC-eta-specific, cDNA probe. The induction of the 4.7-kb PKC-epsilon-related mRNA by IFN-alpha had the following properties reported for the classical IFN-alpha-stimulated genes: rapid kinetics of induction, high maintained levels in IFN-alpha-sensitive but not in IFN-alpha-resistant cell lines, protein synthesis-independent induction, and high sensitivity to inhibitors of protein tyrosine kinase activity. These results show that the regulation of gene expression by IFN-alpha include not only the classical IFN-alpha-stimulated genes but also the coordinated regulation of two PKC-epsilon-related transcripts that appeared to be highly relevant to the biological actions of IFN-alpha.

Full text

PDF
6944

Images in this article

Selected References

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

  1. Bacher N., Zisman Y., Berent E., Livneh E. Isolation and characterization of PKC-L, a new member of the protein kinase C-related gene family specifically expressed in lung, skin, and heart. Mol Cell Biol. 1991 Jan;11(1):126–133. doi: 10.1128/mcb.11.1.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baxter G., Oto E., Daniel-Issakani S., Strulovici B. Constitutive presence of a catalytic fragment of protein kinase C epsilon in a small cell lung carcinoma cell line. J Biol Chem. 1992 Jan 25;267(3):1910–1917. [PubMed] [Google Scholar]
  3. 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]
  4. Dekker L. V., Parker P. J., McIntyre P. Biochemical properties of rat protein kinase C-eta expressed in COS cells. FEBS Lett. 1992 Nov 9;312(2-3):195–199. doi: 10.1016/0014-5793(92)80934-9. [DOI] [PubMed] [Google Scholar]
  5. Faltynek C. R., Princler G. L., Gusella G. L., Varesio L., Radzioch D. A functional protein kinase C is required for induction of 2-5A synthetase by recombinant interferon-alpha A in Daudi cells. J Biol Chem. 1989 Aug 25;264(24):14305–14311. [PubMed] [Google Scholar]
  6. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  7. Friedman R. L., Stark G. R. alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences. Nature. 1985 Apr 18;314(6012):637–639. doi: 10.1038/314637a0. [DOI] [PubMed] [Google Scholar]
  8. Fu X. Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24;70(2):323–335. doi: 10.1016/0092-8674(92)90106-m. [DOI] [PubMed] [Google Scholar]
  9. Fu X. Y., Kessler D. S., Veals S. A., Levy D. E., Darnell J. E., Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555–8559. doi: 10.1073/pnas.87.21.8555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kessler D. S., Pine R., Pfeffer L. M., Levy D. E., Darnell J. E., Jr Cells resistant to interferon are defective in activation of a promoter-binding factor. EMBO J. 1988 Dec 1;7(12):3779–3783. doi: 10.1002/j.1460-2075.1988.tb03262.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Larner A. C., Chaudhuri A., Darnell J. E., Jr Transcriptional induction by interferon. New protein(s) determine the extent and length of the induction. J Biol Chem. 1986 Jan 5;261(1):453–459. [PubMed] [Google Scholar]
  13. McMahon M., Stark G. R., Kerr I. M. Interferon-induced gene expression in wild-type and interferon-resistant human lymphoblastoid (Daudi) cells. J Virol. 1986 Jan;57(1):362–366. doi: 10.1128/jvi.57.1.362-366.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Osada S., Mizuno K., Saido T. C., Akita Y., Suzuki K., Kuroki T., Ohno S. A phorbol ester receptor/protein kinase, nPKC eta, a new member of the protein kinase C family predominantly expressed in lung and skin. J Biol Chem. 1990 Dec 25;265(36):22434–22440. [PubMed] [Google Scholar]
  18. Parker P. J., Kour G., Marais R. M., Mitchell F., Pears C., Schaap D., Stabel S., Webster C. Protein kinase C--a family affair. Mol Cell Endocrinol. 1989 Aug;65(1-2):1–11. doi: 10.1016/0303-7207(89)90159-7. [DOI] [PubMed] [Google Scholar]
  19. Pfeffer L. M., Donner D. B. The down-regulation of alpha-interferon receptors in human lymphoblastoid cells: relation to cellular responsiveness to the antiproliferative action of alpha-interferon. Cancer Res. 1990 May 1;50(9):2654–2657. [PubMed] [Google Scholar]
  20. Pfeffer L. M., Eisenkraft B. L., Reich N. C., Improta T., Baxter G., Daniel-Issakani S., Strulovici B. Transmembrane signaling by interferon alpha involves diacylglycerol production and activation of the epsilon isoform of protein kinase C in Daudi cells. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):7988–7992. doi: 10.1073/pnas.88.18.7988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pfeffer L. M., Strulovici B., Saltiel A. R. Interferon-alpha selectively activates the beta isoform of protein kinase C through phosphatidylcholine hydrolysis. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6537–6541. doi: 10.1073/pnas.87.17.6537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Puissant C., Houdebine L. M. An improvement of the single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Biotechniques. 1990 Feb;8(2):148–149. [PubMed] [Google Scholar]
  23. Reich N. C., Pfeffer L. M. Evidence for involvement of protein kinase C in the cellular response to interferon alpha. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8761–8765. doi: 10.1073/pnas.87.22.8761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Reich N., Evans B., Levy D., Fahey D., Knight E., Jr, Darnell J. E., Jr Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6394–6398. doi: 10.1073/pnas.84.18.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schaap D., Hsuan J., Totty N., Parker P. J. Proteolytic activation of protein kinase C-epsilon. Eur J Biochem. 1990 Jul 31;191(2):431–435. doi: 10.1111/j.1432-1033.1990.tb19139.x. [DOI] [PubMed] [Google Scholar]
  26. Schaap D., Parker P. J., Bristol A., Kriz R., Knopf J. Unique substrate specificity and regulatory properties of PKC-epsilon: a rationale for diversity. FEBS Lett. 1989 Jan 30;243(2):351–357. doi: 10.1016/0014-5793(89)80160-7. [DOI] [PubMed] [Google Scholar]
  27. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  28. Sekiguchi K., Tsukuda M., Ase K., Kikkawa U., Nishizuka Y. Mode of activation and kinetic properties of three distinct forms of protein kinase C from rat brain. J Biochem. 1988 May;103(5):759–765. doi: 10.1093/oxfordjournals.jbchem.a122343. [DOI] [PubMed] [Google Scholar]
  29. Wada H., Ohno S., Kubo K., Taya C., Tsuji S., Yonehara S., Suzuki K. Cell type-specific expression of the genes for the protein kinase C family: down regulation of mRNAs for PKC alpha and nPKC epsilon upon in vitro differentiation of a mouse neuroblastoma cell line neuro 2a. Biochem Biophys Res Commun. 1989 Nov 30;165(1):533–538. doi: 10.1016/0006-291x(89)91102-9. [DOI] [PubMed] [Google Scholar]
  30. Wang C., Li Y., Wible B., Angelides K. J., Ishii D. N. Effects of insulin and insulin-like growth factors on neurofilament mRNA and tubulin mRNA content in human neuroblastoma SH-SY5Y cells. Brain Res Mol Brain Res. 1992 May;13(4):289–300. doi: 10.1016/0169-328x(92)90212-t. [DOI] [PubMed] [Google Scholar]
  31. Wetsel W. C., Khan W. A., Merchenthaler I., Rivera H., Halpern A. E., Phung H. M., Negro-Vilar A., Hannun Y. A. Tissue and cellular distribution of the extended family of protein kinase C isoenzymes. J Cell Biol. 1992 Apr;117(1):121–133. doi: 10.1083/jcb.117.1.121. [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