Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Jan;17(1):170–181. doi: 10.1128/mcb.17.1.170

Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis.

J M Lenczowski 1, L Dominguez 1, A M Eder 1, L B King 1, C M Zacharchuk 1, J D Ashwell 1
PMCID: PMC231741  PMID: 8972197

Abstract

Cross-linking of Fas (CD95) induces apoptosis, a response that has been reported to depend upon the Ras activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activating enzyme Jun kinase (JNK), downstream effectors of Ras or Ras-like small GTP-binding proteins, we evaluated the role of these molecules in Fas-mediated apoptosis. Although cross-linking of Fas on Jurkat T cells did result in JNK activation, increased activity was observed relatively late, being detectable only after 60 min of stimulation. Expression of a dominant negative form of SEK1 that blocked Fas-mediated induction of JNK activity had no effect on Fas-mediated apoptosis. Furthermore, maximally effective concentrations of anti-Fas did not cause JNK activation if apoptosis was blocked by a cysteine protease inhibitor, suggesting that under these conditions, activation of JNK may be secondary to the stress of apoptosis rather than a direct result of Fas engagement. Despite the activation of JNK, there was no induction of AP-1 activity as determined by gel shift assay or induction of an AP-1-responsive reporter. The lack of a requirement for AP-1 induction in Fas-mediated death was further substantiated with Jurkat cells that were stably transfected with a dominant negative cJun, TAM-67. While TAM-67 effectively prevented AP-1-dependent transcription of both the interleukin-2 and cJun genes, it had no effect on Fas-induced cell death, even at limiting levels of Fas signaling. Thus, induction of JNK activity in Jurkat cells by ligation of Fas at levels sufficient to cause cell death is likely a result, rather than a cause, of the apoptotic response, and AP-1 function is not required for Fas-induced apoptosis.

Full Text

The Full Text of this article is available as a PDF (523.4 KB).

Selected References

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

  1. Alani R., Brown P., Binétruy B., Dosaka H., Rosenberg R. K., Angel P., Karin M., Birrer M. J. The transactivating domain of the c-Jun proto-oncoprotein is required for cotransformation of rat embryo cells. Mol Cell Biol. 1991 Dec;11(12):6286–6295. doi: 10.1128/mcb.11.12.6286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Angel P., Hattori K., Smeal T., Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. doi: 10.1016/0092-8674(88)90143-2. [DOI] [PubMed] [Google Scholar]
  3. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  4. Auwerx J., Sassone-Corsi P. AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth. Oncogene. 1992 Nov;7(11):2271–2280. [PubMed] [Google Scholar]
  5. Auwerx J., Sassone-Corsi P. IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. Cell. 1991 Mar 8;64(5):983–993. doi: 10.1016/0092-8674(91)90322-p. [DOI] [PubMed] [Google Scholar]
  6. Baldari C. T., Heguy A., Telford J. L. ras protein activity is essential for T-cell antigen receptor signal transduction. J Biol Chem. 1993 Feb 5;268(4):2693–2698. [PubMed] [Google Scholar]
  7. Bassuk A. G., Leiden J. M. A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity. 1995 Aug;3(2):223–237. doi: 10.1016/1074-7613(95)90092-6. [DOI] [PubMed] [Google Scholar]
  8. Binétruy B., Smeal T., Karin M. Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature. 1991 May 9;351(6322):122–127. doi: 10.1038/351122a0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Boldin M. P., Varfolomeev E. E., Pancer Z., Mett I. L., Camonis J. H., Wallach D. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem. 1995 Apr 7;270(14):7795–7798. doi: 10.1074/jbc.270.14.7795. [DOI] [PubMed] [Google Scholar]
  11. Boyle W. J., Smeal T., Defize L. H., Angel P., Woodgett J. R., Karin M., Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573–584. doi: 10.1016/0092-8674(91)90241-p. [DOI] [PubMed] [Google Scholar]
  12. Brown P. H., Alani R., Preis L. H., Szabo E., Birrer M. J. Suppression of oncogene-induced transformation by a deletion mutant of c-jun. Oncogene. 1993 Apr;8(4):877–886. [PubMed] [Google Scholar]
  13. Brown P. H., Chen T. K., Birrer M. J. Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene. 1994 Mar;9(3):791–799. [PubMed] [Google Scholar]
  14. Chinnaiyan A. M., O'Rourke K., Tewari M., Dixit V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505–512. doi: 10.1016/0092-8674(95)90071-3. [DOI] [PubMed] [Google Scholar]
  15. Coso O. A., Chiariello M., Kalinec G., Kyriakis J. M., Woodgett J., Gutkind J. S. Transforming G protein-coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway. J Biol Chem. 1995 Mar 10;270(10):5620–5624. doi: 10.1074/jbc.270.10.5620. [DOI] [PubMed] [Google Scholar]
  16. Coso O. A., Chiariello M., Yu J. C., Teramoto H., Crespo P., Xu N., Miki T., Gutkind J. S. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995 Jun 30;81(7):1137–1146. doi: 10.1016/s0092-8674(05)80018-2. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Davis R. J. MAPKs: new JNK expands the group. Trends Biochem Sci. 1994 Nov;19(11):470–473. doi: 10.1016/0968-0004(94)90132-5. [DOI] [PubMed] [Google Scholar]
  19. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  20. Domann F. E., Levy J. P., Birrer M. J., Bowden G. T. Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice. Cell Growth Differ. 1994 Jan;5(1):9–16. [PubMed] [Google Scholar]
  21. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  22. Goldstone S. D., Lavin M. F. Prolonged expression of c-jun and associated activity of the transcription factor AP-1, during apoptosis in a human leukaemic cell line. Oncogene. 1994 Aug;9(8):2305–2311. [PubMed] [Google Scholar]
  23. Gulbins E., Bissonnette R., Mahboubi A., Martin S., Nishioka W., Brunner T., Baier G., Baier-Bitterlich G., Byrd C., Lang F. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity. 1995 Apr;2(4):341–351. doi: 10.1016/1074-7613(95)90142-6. [DOI] [PubMed] [Google Scholar]
  24. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  25. Haimovitz-Friedman A., Kan C. C., Ehleiter D., Persaud R. S., McLoughlin M., Fuks Z., Kolesnick R. N. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994 Aug 1;180(2):525–535. doi: 10.1084/jem.180.2.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  27. Hirai S. I., Ryseck R. P., Mechta F., Bravo R., Yaniv M. Characterization of junD: a new member of the jun proto-oncogene family. EMBO J. 1989 May;8(5):1433–1439. doi: 10.1002/j.1460-2075.1989.tb03525.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hirai S., Izumi Y., Higa K., Kaibuchi K., Mizuno K., Osada S., Suzuki K., Ohno S. Ras-dependent signal transduction is indispensable but not sufficient for the activation of AP1/Jun by PKC delta. EMBO J. 1994 May 15;13(10):2331–2340. doi: 10.1002/j.1460-2075.1994.tb06517.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Imler J. L., Schatz C., Wasylyk C., Chatton B., Wasylyk B. A Harvey-ras responsive transcription element is also responsive to a tumour-promoter and to serum. Nature. 1988 Mar 17;332(6161):275–278. doi: 10.1038/332275a0. [DOI] [PubMed] [Google Scholar]
  30. Jain J., McCaffrey P. G., Miner Z., Kerppola T. K., Lambert J. N., Verdine G. L., Curran T., Rao A. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993 Sep 23;365(6444):352–355. doi: 10.1038/365352a0. [DOI] [PubMed] [Google Scholar]
  31. Jain V. K., Magrath I. T. A chemiluminescent assay for quantitation of beta-galactosidase in the femtogram range: application to quantitation of beta-galactosidase in lacZ-transfected cells. Anal Biochem. 1991 Nov 15;199(1):119–124. doi: 10.1016/0003-2697(91)90278-2. [DOI] [PubMed] [Google Scholar]
  32. Johnson N. L., Gardner A. M., Diener K. M., Lange-Carter C. A., Gleavy J., Jarpe M. B., Minden A., Karin M., Zon L. I., Johnson G. L. Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death. J Biol Chem. 1996 Feb 9;271(6):3229–3237. doi: 10.1074/jbc.271.6.3229. [DOI] [PubMed] [Google Scholar]
  33. Kim M. Y., Linardic C., Obeid L., Hannun Y. Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation. J Biol Chem. 1991 Jan 5;266(1):484–489. [PubMed] [Google Scholar]
  34. Kischkel F. C., Hellbardt S., Behrmann I., Germer M., Pawlita M., Krammer P. H., Peter M. E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995 Nov 15;14(22):5579–5588. doi: 10.1002/j.1460-2075.1995.tb00245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Latinis K. M., Koretzky G. A. Fas ligation induces apoptosis and Jun kinase activation independently of CD45 and Lck in human T cells. Blood. 1996 Feb 1;87(3):871–875. [PubMed] [Google Scholar]
  36. Leonard W. J., Depper J. M., Crabtree G. R., Rudikoff S., Pumphrey J., Robb R. J., Krönke M., Svetlik P. B., Peffer N. J., Waldmann T. A. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. doi: 10.1038/311626a0. [DOI] [PubMed] [Google Scholar]
  37. Lin A., Frost J., Deng T., Smeal T., al-Alawi N., Kikkawa U., Hunter T., Brenner D., Karin M. Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity. Cell. 1992 Sep 4;70(5):777–789. doi: 10.1016/0092-8674(92)90311-y. [DOI] [PubMed] [Google Scholar]
  38. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  39. MacGregor G. R., Caskey C. T. Construction of plasmids that express E. coli beta-galactosidase in mammalian cells. Nucleic Acids Res. 1989 Mar 25;17(6):2365–2365. doi: 10.1093/nar/17.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  41. Martin S. J. Apoptosis: suicide, execution or murder? Trends Cell Biol. 1993 May;3(5):141–144. doi: 10.1016/0962-8924(93)90128-n. [DOI] [PubMed] [Google Scholar]
  42. Martin S. J., Reutelingsperger C. P., McGahon A. J., Rader J. A., van Schie R. C., LaFace D. M., Green D. R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995 Nov 1;182(5):1545–1556. doi: 10.1084/jem.182.5.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. McCaffrey P. G., Luo C., Kerppola T. K., Jain J., Badalian T. M., Ho A. M., Burgeon E., Lane W. S., Lambert J. N., Curran T. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science. 1993 Oct 29;262(5134):750–754. doi: 10.1126/science.8235597. [DOI] [PubMed] [Google Scholar]
  44. Memon S. A., Petrak D., Moreno M. B., Zacharchuk C. M. A simple assay for examining the effect of transiently expressed genes on programmed cell death. J Immunol Methods. 1995 Mar 13;180(1):15–24. doi: 10.1016/0022-1759(94)00294-7. [DOI] [PubMed] [Google Scholar]
  45. Merćep M., Bluestone J. A., Noguchi P. D., Ashwell J. D. Inhibition of transformed T cell growth in vitro by monoclonal antibodies directed against distinct activating molecules. J Immunol. 1988 Jan 1;140(1):324–335. [PubMed] [Google Scholar]
  46. Minden A., Lin A., Claret F. X., Abo A., Karin M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell. 1995 Jun 30;81(7):1147–1157. doi: 10.1016/s0092-8674(05)80019-4. [DOI] [PubMed] [Google Scholar]
  47. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  48. Minden A., Lin A., Smeal T., Dérijard B., Cobb M., Davis R., Karin M. c-Jun N-terminal phosphorylation correlates with activation of the JNK subgroup but not the ERK subgroup of mitogen-activated protein kinases. Mol Cell Biol. 1994 Oct;14(10):6683–6688. doi: 10.1128/mcb.14.10.6683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  51. Northrop J. P., Ho S. N., Chen L., Thomas D. J., Timmerman L. A., Nolan G. P., Admon A., Crabtree G. R. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature. 1994 Jun 9;369(6480):497–502. doi: 10.1038/369497a0. [DOI] [PubMed] [Google Scholar]
  52. Petrak D., Memon S. A., Birrer M. J., Ashwell J. D., Zacharchuk C. M. Dominant negative mutant of c-Jun inhibits NF-AT transcriptional activity and prevents IL-2 gene transcription. J Immunol. 1994 Sep 1;153(5):2046–2051. [PubMed] [Google Scholar]
  53. Ponta H., Cato A. C., Herrlich P. Interference of pathway specific transcription factors. Biochim Biophys Acta. 1992 Feb 11;1129(3):255–261. doi: 10.1016/0167-4781(92)90501-p. [DOI] [PubMed] [Google Scholar]
  54. Pronk G. J., Ramer K., Amiri P., Williams L. T. Requirement of an ICE-like protease for induction of apoptosis and ceramide generation by REAPER. Science. 1996 Feb 9;271(5250):808–810. doi: 10.1126/science.271.5250.808. [DOI] [PubMed] [Google Scholar]
  55. Raines M. A., Kolesnick R. N., Golde D. W. Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells. J Biol Chem. 1993 Jul 15;268(20):14572–14575. [PubMed] [Google Scholar]
  56. Roffler-Tarlov S., Brown J. J., Tarlov E., Stolarov J., Chapman D. L., Alexiou M., Papaioannou V. E. Programmed cell death in the absence of c-Fos and c-Jun. Development. 1996 Jan;122(1):1–9. doi: 10.1242/dev.122.1.1. [DOI] [PubMed] [Google Scholar]
  57. Sassone-Corsi P., Lamph W. W., Kamps M., Verma I. M. fos-associated cellular p39 is related to nuclear transcription factor AP-1. Cell. 1988 Aug 12;54(4):553–560. doi: 10.1016/0092-8674(88)90077-3. [DOI] [PubMed] [Google Scholar]
  58. Sato T., Irie S., Kitada S., Reed J. C. FAP-1: a protein tyrosine phosphatase that associates with Fas. Science. 1995 Apr 21;268(5209):411–415. doi: 10.1126/science.7536343. [DOI] [PubMed] [Google Scholar]
  59. Sawai H., Okazaki T., Yamamoto H., Okano H., Takeda Y., Tashima M., Sawada H., Okuma M., Ishikura H., Umehara H. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem. 1995 Nov 10;270(45):27326–27331. doi: 10.1074/jbc.270.45.27326. [DOI] [PubMed] [Google Scholar]
  60. Schlegel J., Peters I., Orrenius S. Isolation and partial characterization of a protease involved in Fas-induced apoptosis. FEBS Lett. 1995 May 8;364(2):139–142. doi: 10.1016/0014-5793(95)00374-i. [DOI] [PubMed] [Google Scholar]
  61. Schlegel J., Peters I., Orrenius S., Miller D. K., Thornberry N. A., Yamin T. T., Nicholson D. W. CPP32/apopain is a key interleukin 1 beta converting enzyme-like protease involved in Fas-mediated apoptosis. J Biol Chem. 1996 Jan 26;271(4):1841–1844. doi: 10.1074/jbc.271.4.1841. [DOI] [PubMed] [Google Scholar]
  62. Seger R., Krebs E. G. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed] [Google Scholar]
  63. Sistonen L., Hölttä E., Mäkelä T. P., Keski-Oja J., Alitalo K. The cellular response to induction of the p21 c-Ha-ras oncoprotein includes stimulation of jun gene expression. EMBO J. 1989 Mar;8(3):815–822. doi: 10.1002/j.1460-2075.1989.tb03442.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Smeal T., Binetruy B., Mercola D. A., Birrer M., Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature. 1991 Dec 12;354(6353):494–496. doi: 10.1038/354494a0. [DOI] [PubMed] [Google Scholar]
  65. Stanger B. Z., Leder P., Lee T. H., Kim E., Seed B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 1995 May 19;81(4):513–523. doi: 10.1016/0092-8674(95)90072-1. [DOI] [PubMed] [Google Scholar]
  66. Stein B., Baldwin A. S., Jr, Ballard D. W., Greene W. C., Angel P., Herrlich P. Cross-coupling of the NF-kappa B p65 and Fos/Jun transcription factors produces potentiated biological function. EMBO J. 1993 Oct;12(10):3879–3891. doi: 10.1002/j.1460-2075.1993.tb06066.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Su B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. JNK is involved in signal integration during costimulation of T lymphocytes. Cell. 1994 Jun 3;77(5):727–736. doi: 10.1016/0092-8674(94)90056-6. [DOI] [PubMed] [Google Scholar]
  68. Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
  69. Tepper C. G., Jayadev S., Liu B., Bielawska A., Wolff R., Yonehara S., Hannun Y. A., Seldin M. F. Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8443–8447. doi: 10.1073/pnas.92.18.8443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Tian Q., Streuli M., Saito H., Schlossman S. F., Anderson P. A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell. 1991 Nov 1;67(3):629–639. doi: 10.1016/0092-8674(91)90536-8. [DOI] [PubMed] [Google Scholar]
  71. Tian Q., Taupin J., Elledge S., Robertson M., Anderson P. Fas-activated serine/threonine kinase (FAST) phosphorylates TIA-1 during Fas-mediated apoptosis. J Exp Med. 1995 Sep 1;182(3):865–874. doi: 10.1084/jem.182.3.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Uberall F., Kampfer S., Doppler W., Grunicke H. H. Activation of c-fos expression by transforming Ha-ras in HC11 mouse mammary epithelial cells is PKC-dependent and mediated by the serum response element. Cell Signal. 1994 Mar;6(3):285–297. doi: 10.1016/0898-6568(94)90033-7. [DOI] [PubMed] [Google Scholar]
  73. Uchiyama T., Broder S., Waldmann T. A. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol. 1981 Apr;126(4):1393–1397. [PubMed] [Google Scholar]
  74. Ullman K. S., Northrop J. P., Admon A., Crabtree G. R. Jun family members are controlled by a calcium-regulated, cyclosporin A-sensitive signaling pathway in activated T lymphocytes. Genes Dev. 1993 Feb;7(2):188–196. doi: 10.1101/gad.7.2.188. [DOI] [PubMed] [Google Scholar]
  75. 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]
  76. Westwick J. K., Bielawska A. E., Dbaibo G., Hannun Y. A., Brenner D. A. Ceramide activates the stress-activated protein kinases. J Biol Chem. 1995 Sep 29;270(39):22689–22692. doi: 10.1074/jbc.270.39.22689. [DOI] [PubMed] [Google Scholar]
  77. Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. doi: 10.1126/science.7618106. [DOI] [PubMed] [Google Scholar]
  78. 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]
  79. Yamauchi K., Holt K., Pessin J. E. Phosphatidylinositol 3-kinase functions upstream of Ras and Raf in mediating insulin stimulation of c-fos transcription. J Biol Chem. 1993 Jul 15;268(20):14597–14600. [PubMed] [Google Scholar]
  80. Yang Y., Merćep M., Ware C. F., Ashwell J. D. Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids. J Exp Med. 1995 May 1;181(5):1673–1682. doi: 10.1084/jem.181.5.1673. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES