Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Aug;17(8):4346–4354. doi: 10.1128/mcb.17.8.4346

Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade.

E Berra 1, M M Municio 1, L Sanz 1, S Frutos 1, M T Diaz-Meco 1, J Moscat 1
PMCID: PMC232288  PMID: 9234692

Abstract

Recent studies have documented the involvement of the atypical protein kinase C (aPKC) isoforms in important cellular functions such as cell proliferation and survival. Exposure of cells to a genotoxic stimulus that induces apoptosis, such as UV irradiation, leads to a profound inhibition of the atypical PKC activity in vivo. In this study, we addressed the relationship between this phenomenon and different proteins involved in the apoptotic response. We show that (i) the inhibition of the aPKC activity precedes UV-induced apoptosis; (ii) UV-induced aPKC inhibition and apoptosis are independent of p53; (iii) Bcl-2 proteins are potent modulators of aPKC activity; and (iv) the aPKCs are located upstream of the interleukin-converting enzyme-like protease system, which is required for the induction of apoptosis by both Par-4 (a selective aPKC inhibitor) and UV irradiation. We also demonstrate here that inhibition of aPKC activity leads to a decrease in mitogen-activated protein (MAP) kinase activity and simultaneously an increase in p38 activity. Both effects are critical for the induction of apoptosis in response to Par-4 expression and UV irradiation. Collectively, these results clarify the position of the aPKCs in the UV-induced apoptotic pathway and strongly suggest that MAP kinases play a role in this signaling cascade.

Full Text

The Full Text of this article is available as a PDF (783.6 KB).

Selected References

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

  1. Akimoto K., Mizuno K., Osada S., Hirai S., Tanuma S., Suzuki K., Ohno S. A new member of the third class in the protein kinase C family, PKC lambda, expressed dominantly in an undifferentiated mouse embryonal carcinoma cell line and also in many tissues and cells. J Biol Chem. 1994 Apr 29;269(17):12677–12683. [PubMed] [Google Scholar]
  2. Akimoto K., Takahashi R., Moriya S., Nishioka N., Takayanagi J., Kimura K., Fukui Y., Osada S. i., Mizuno K., Hirai S. i. EGF or PDGF receptors activate atypical PKClambda through phosphatidylinositol 3-kinase. EMBO J. 1996 Feb 15;15(4):788–798. [PMC free article] [PubMed] [Google Scholar]
  3. Attardi L. D., Lowe S. W., Brugarolas J., Jacks T. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. EMBO J. 1996 Jul 15;15(14):3693–3701. [PMC free article] [PubMed] [Google Scholar]
  4. Bandyopadhyay G., Standaert M. L., Zhao L., Yu B., Avignon A., Galloway L., Karnam P., Moscat J., Farese R. V. Activation of protein kinase C (alpha, beta, and zeta) by insulin in 3T3/L1 cells. Transfection studies suggest a role for PKC-zeta in glucose transport. J Biol Chem. 1997 Jan 24;272(4):2551–2558. doi: 10.1074/jbc.272.4.2551. [DOI] [PubMed] [Google Scholar]
  5. Berra E., Diaz-Meco M. T., Dominguez I., Municio M. M., Sanz L., Lozano J., Chapkin R. S., Moscat J. Protein kinase C zeta isoform is critical for mitogenic signal transduction. Cell. 1993 Aug 13;74(3):555–563. doi: 10.1016/0092-8674(93)80056-k. [DOI] [PubMed] [Google Scholar]
  6. Berra E., Díaz-Meco M. T., Lozano J., Frutos S., Municio M. M., Sánchez P., Sanz L., Moscat J. Evidence for a role of MEK and MAPK during signal transduction by protein kinase C zeta. EMBO J. 1995 Dec 15;14(24):6157–6163. doi: 10.1002/j.1460-2075.1995.tb00306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bjorkoy G., Perander M., Overvatn A., Johansen T. Reversion of Ras- and phosphatidylcholine-hydrolyzing phospholipase C-mediated transformation of NIH 3T3 cells by a dominant interfering mutant of protein kinase C lambda is accompanied by the loss of constitutive nuclear mitogen-activated protein kinase/extracellular signal-regulated kinase activity. J Biol Chem. 1997 Apr 25;272(17):11557–11565. doi: 10.1074/jbc.272.17.11557. [DOI] [PubMed] [Google Scholar]
  8. Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
  9. Canman C. E., Kastan M. B. Signal transduction. Three paths to stress relief. Nature. 1996 Nov 21;384(6606):213–214. doi: 10.1038/384213a0. [DOI] [PubMed] [Google Scholar]
  10. Chen Y. R., Wang X., Templeton D., Davis R. J., Tan T. H. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem. 1996 Dec 13;271(50):31929–31936. doi: 10.1074/jbc.271.50.31929. [DOI] [PubMed] [Google Scholar]
  11. Chinnaiyan A. M., Orth K., O'Rourke K., Duan H., Poirier G. G., Dixit V. M. Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. J Biol Chem. 1996 Mar 1;271(9):4573–4576. doi: 10.1074/jbc.271.9.4573. [DOI] [PubMed] [Google Scholar]
  12. Diaz-Meco M. T., Berra E., Municio M. M., Sanz L., Lozano J., Dominguez I., Diaz-Golpe V., Lain de Lera M. T., Alcamí J., Payá C. V. A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation. Mol Cell Biol. 1993 Aug;13(8):4770–4775. doi: 10.1128/mcb.13.8.4770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Diaz-Meco M. T., Lozano J., Municio M. M., Berra E., Frutos S., Sanz L., Moscat J. Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta. J Biol Chem. 1994 Dec 16;269(50):31706–31710. [PubMed] [Google Scholar]
  14. Diaz-Meco M. T., Municio M. M., Sanchez P., Lozano J., Moscat J. Lambda-interacting protein, a novel protein that specifically interacts with the zinc finger domain of the atypical protein kinase C isotype lambda/iota and stimulates its kinase activity in vitro and in vivo. Mol Cell Biol. 1996 Jan;16(1):105–114. doi: 10.1128/mcb.16.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dominguez I., Diaz-Meco M. T., Municio M. M., Berra E., García de Herreros A., Cornet M. E., Sanz L., Moscat J. Evidence for a role of protein kinase C zeta subspecies in maturation of Xenopus laevis oocytes. Mol Cell Biol. 1992 Sep;12(9):3776–3783. doi: 10.1128/mcb.12.9.3776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dominguez I., Sanz L., Arenzana-Seisdedos F., Diaz-Meco M. T., Virelizier J. L., Moscat J. Inhibition of protein kinase C zeta subspecies blocks the activation of an NF-kappa B-like activity in Xenopus laevis oocytes. Mol Cell Biol. 1993 Feb;13(2):1290–1295. doi: 10.1128/mcb.13.2.1290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Díaz-Meco M. T., Municio M. M., Frutos S., Sanchez P., Lozano J., Sanz L., Moscat J. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell. 1996 Sep 6;86(5):777–786. doi: 10.1016/s0092-8674(00)80152-x. [DOI] [PubMed] [Google Scholar]
  18. Exton J. H. Phosphatidylcholine breakdown and signal transduction. Biochim Biophys Acta. 1994 Apr 14;1212(1):26–42. doi: 10.1016/0005-2760(94)90186-4. [DOI] [PubMed] [Google Scholar]
  19. Farrow S. N., Brown R. New members of the Bcl-2 family and their protein partners. Curr Opin Genet Dev. 1996 Feb;6(1):45–49. doi: 10.1016/s0959-437x(96)90009-x. [DOI] [PubMed] [Google Scholar]
  20. Folgueira L., McElhinny J. A., Bren G. D., MacMorran W. S., Diaz-Meco M. T., Moscat J., Paya C. V. Protein kinase C-zeta mediates NF-kappa B activation in human immunodeficiency virus-infected monocytes. J Virol. 1996 Jan;70(1):223–231. doi: 10.1128/jvi.70.1.223-231.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fraser A., Evan G. A license to kill. Cell. 1996 Jun 14;85(6):781–784. doi: 10.1016/s0092-8674(00)81005-3. [DOI] [PubMed] [Google Scholar]
  22. Gottlieb T. M., Oren M. p53 in growth control and neoplasia. Biochim Biophys Acta. 1996 Jun 7;1287(2-3):77–102. doi: 10.1016/0304-419x(95)00019-c. [DOI] [PubMed] [Google Scholar]
  23. Hannun Y. A. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem. 1994 Feb 4;269(5):3125–3128. [PubMed] [Google Scholar]
  24. Henkart P. A. ICE family proteases: mediators of all apoptotic cell death? Immunity. 1996 Mar;4(3):195–201. doi: 10.1016/s1074-7613(00)80428-8. [DOI] [PubMed] [Google Scholar]
  25. Huang C., Ma W. y., Bowden G. T., Dong Z. Ultraviolet B-induced activated protein-1 activation does not require epidermal growth factor receptor but is blocked by a dominant negative PKClambda/iota. J Biol Chem. 1996 Dec 6;271(49):31262–31268. doi: 10.1074/jbc.271.49.31262. [DOI] [PubMed] [Google Scholar]
  26. Johnstone R. W., See R. H., Sells S. F., Wang J., Muthukkumar S., Englert C., Haber D. A., Licht J. D., Sugrue S. P., Roberts T. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Mol Cell Biol. 1996 Dec;16(12):6945–6956. doi: 10.1128/mcb.16.12.6945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ko L. J., Prives C. p53: puzzle and paradigm. Genes Dev. 1996 May 1;10(9):1054–1072. doi: 10.1101/gad.10.9.1054. [DOI] [PubMed] [Google Scholar]
  28. Kolesnick R., Golde D. W. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell. 1994 May 6;77(3):325–328. doi: 10.1016/0092-8674(94)90147-3. [DOI] [PubMed] [Google Scholar]
  29. Kulik G., Klippel A., Weber M. J. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997 Mar;17(3):1595–1606. doi: 10.1128/mcb.17.3.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kyriakis J. M., Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem. 1996 Oct 4;271(40):24313–24316. doi: 10.1074/jbc.271.40.24313. [DOI] [PubMed] [Google Scholar]
  31. Limatola C., Barabino B., Nista A., Santoni A. Interleukin 1-beta-induced protein kinase C-zeta activation is mimicked by exogenous phospholipase D. Biochem J. 1997 Jan 15;321(Pt 2):497–501. doi: 10.1042/bj3210497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Liscovitch M., Cantley L. C. Lipid second messengers. Cell. 1994 May 6;77(3):329–334. doi: 10.1016/0092-8674(94)90148-1. [DOI] [PubMed] [Google Scholar]
  33. Liu Z. G., Baskaran R., Lea-Chou E. T., Wood L. D., Chen Y., Karin M., Wang J. Y. Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature. 1996 Nov 21;384(6606):273–276. doi: 10.1038/384273a0. [DOI] [PubMed] [Google Scholar]
  34. Liu Z. G., Hsu H., Goeddel D. V., Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell. 1996 Nov 1;87(3):565–576. doi: 10.1016/s0092-8674(00)81375-6. [DOI] [PubMed] [Google Scholar]
  35. Long S. D., Pekala P. H. Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochem J. 1996 Oct 1;319(Pt 1):179–184. doi: 10.1042/bj3190179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lotem J., Sachs L. Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12507–12512. doi: 10.1073/pnas.93.22.12507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lozano J., Berra E., Municio M. M., Diaz-Meco M. T., Dominguez I., Sanz L., Moscat J. Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J Biol Chem. 1994 Jul 29;269(30):19200–19202. [PubMed] [Google Scholar]
  38. Miyashita T., Reed J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. doi: 10.1016/0092-8674(95)90412-3. [DOI] [PubMed] [Google Scholar]
  39. Muzio M., Chinnaiyan A. M., Kischkel F. C., O'Rourke K., Shevchenko A., Ni J., Scaffidi C., Bretz J. D., Zhang M., Gentz R. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817–827. doi: 10.1016/s0092-8674(00)81266-0. [DOI] [PubMed] [Google Scholar]
  40. Nakanishi H., Brewer K. A., Exton J. H. Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1993 Jan 5;268(1):13–16. [PubMed] [Google Scholar]
  41. Nakanishi H., Exton J. H. Purification and characterization of the zeta isoform of protein kinase C from bovine kidney. J Biol Chem. 1992 Aug 15;267(23):16347–16354. [PubMed] [Google Scholar]
  42. 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]
  43. Oltvai Z. N., Korsmeyer S. J. Checkpoints of dueling dimers foil death wishes. Cell. 1994 Oct 21;79(2):189–192. doi: 10.1016/0092-8674(94)90188-0. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Párrizas M., Saltiel A. R., LeRoith D. Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. J Biol Chem. 1997 Jan 3;272(1):154–161. doi: 10.1074/jbc.272.1.154. [DOI] [PubMed] [Google Scholar]
  46. Raingeaud J., Whitmarsh A. J., Barrett T., Dérijard B., Davis R. J. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247–1255. doi: 10.1128/mcb.16.3.1247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rosette C., Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science. 1996 Nov 15;274(5290):1194–1197. doi: 10.1126/science.274.5290.1194. [DOI] [PubMed] [Google Scholar]
  48. Rzymkiewicz D. M., Tetsuka T., Daphna-Iken D., Srivastava S., Morrison A. R. Interleukin-1beta activates protein kinase C zeta in renal mesangial cells. Potential role in prostaglandin E2 up-regulation. J Biol Chem. 1996 Jul 19;271(29):17241–17246. doi: 10.1074/jbc.271.29.17241. [DOI] [PubMed] [Google Scholar]
  49. Schreiber M., Baumann B., Cotten M., Angel P., Wagner E. F. Fos is an essential component of the mammalian UV response. EMBO J. 1995 Nov 1;14(21):5338–5349. doi: 10.1002/j.1460-2075.1995.tb00218.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Selbie L. A., Schmitz-Peiffer C., Sheng Y., Biden T. J. Molecular cloning and characterization of PKC iota, an atypical isoform of protein kinase C derived from insulin-secreting cells. J Biol Chem. 1993 Nov 15;268(32):24296–24302. [PubMed] [Google Scholar]
  51. Sells S. F., Wood D. P., Jr, Joshi-Barve S. S., Muthukumar S., Jacob R. J., Crist S. A., Humphreys S., Rangnekar V. M. Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ. 1994 Apr;5(4):457–466. [PubMed] [Google Scholar]
  52. Verheij M., Bose R., Lin X. H., Yao B., Jarvis W. D., Grant S., Birrer M. J., Szabo E., Zon L. I., Kyriakis J. M. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature. 1996 Mar 7;380(6569):75–79. doi: 10.1038/380075a0. [DOI] [PubMed] [Google Scholar]
  53. Wang H. G., Rapp U. R., Reed J. C. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell. 1996 Nov 15;87(4):629–638. doi: 10.1016/s0092-8674(00)81383-5. [DOI] [PubMed] [Google Scholar]
  54. Wooten M. W., Seibenhener M. L., Matthews L. H., Zhou G., Coleman E. S. Modulation of zeta-protein kinase C by cyclic AMP in PC12 cells occurs through phosphorylation by protein kinase A. J Neurochem. 1996 Sep;67(3):1023–1031. doi: 10.1046/j.1471-4159.1996.67031023.x. [DOI] [PubMed] [Google Scholar]
  55. Wooten M. W., Zhou G., Seibenhener M. L., Coleman E. S. A role for zeta protein kinase C in nerve growth factor-induced differentiation of PC12 cells. Cell Growth Differ. 1994 Apr;5(4):395–403. [PubMed] [Google Scholar]
  56. Xia Z., Dickens M., Raingeaud J., Davis R. J., Greenberg M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. doi: 10.1126/science.270.5240.1326. [DOI] [PubMed] [Google Scholar]
  57. Xu J., Clark R. A. A three-dimensional collagen lattice induces protein kinase C-zeta activity: role in alpha2 integrin and collagenase mRNA expression. J Cell Biol. 1997 Jan 27;136(2):473–483. doi: 10.1083/jcb.136.2.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Xu J., Zutter M. M., Santoro S. A., Clark R. A. PDGF induction of alpha 2 integrin gene expression is mediated by protein kinase C-zeta. J Cell Biol. 1996 Sep;134(5):1301–1311. doi: 10.1083/jcb.134.5.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Xu Y., Baltimore D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 1996 Oct 1;10(19):2401–2410. doi: 10.1101/gad.10.19.2401. [DOI] [PubMed] [Google Scholar]
  60. Yao R., Cooper G. M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science. 1995 Mar 31;267(5206):2003–2006. doi: 10.1126/science.7701324. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES