Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling (original) (raw)

Abstract

The dsRNA-dependent protein kinase (PKR) is considered to play a key role in interferon-mediated host defense against viral infection and conceivably malignant transformation. To investigate further the mechanisms of PKR-induced growth inhibition, we have developed tetracycline-inducible murine cell lines that express wild-type PKR or a catalytically inactive PKR variant, PKRdelta6. Following induction, the growth of the wild-type PKR-expressing cells was similar to that of cells transfected with vector alone, while cells expressing PKRdelta6 became malignantly transformed. Significantly, treatment with dsRNA caused the wild-type PKR-overexpressing cells to undergo programed cell death while, conversely, cells expressing PKRdelta6 were completely resistant. Our studies demonstrated that activation of PKR induces the expression of members of the tumor necrosis factor receptor (TNFR) family, including Fas (CD95/Apo-1) and pro-apopotic Bax. In contrast, transcripts representing Fas, TNFR-1, FADD (Fas-associated death domain), FLICE, Bad and Bax were ablated in cells expressing PKRdelta6. The involvement of the death receptors in PKR-induced apoptosis was underscored by demonstrating that murine fibroblasts lacking FADD were almost completely resistant to dsRNA-mediated cell death. Thus, PKR, a key cellular target for viral repression, is a receptor/inducer for the induction of pro-apoptotic genes by dsRNA and probably functions in interferon-mediated host defense to trigger cell death in response to virus infection and perhaps tumorigenesis.

Full Text

The Full Text of this article is available as a PDF (678.6 KB).

Selected References

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

  1. Adachi S., Cross A. R., Babior B. M., Gottlieb R. A. Bcl-2 and the outer mitochondrial membrane in the inactivation of cytochrome c during Fas-mediated apoptosis. J Biol Chem. 1997 Aug 29;272(35):21878–21882. doi: 10.1074/jbc.272.35.21878. [DOI] [PubMed] [Google Scholar]
  2. Amarante-Mendes G. P., Naekyung Kim C., Liu L., Huang Y., Perkins C. L., Green D. R., Bhalla K. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. Blood. 1998 Mar 1;91(5):1700–1705. [PubMed] [Google Scholar]
  3. Barber G. N., Jagus R., Meurs E. F., Hovanessian A. G., Katze M. G. Molecular mechanisms responsible for malignant transformation by regulatory and catalytic domain variants of the interferon-induced enzyme RNA-dependent protein kinase. J Biol Chem. 1995 Jul 21;270(29):17423–17428. doi: 10.1074/jbc.270.29.17423. [DOI] [PubMed] [Google Scholar]
  4. Barber G. N., Tomita J., Garfinkel M. S., Meurs E., Hovanessian A., Katze M. G. Detection of protein kinase homologues and viral RNA-binding domains utilizing polyclonal antiserum prepared against a baculovirus-expressed ds RNA-activated 68,000-Da protein kinase. Virology. 1992 Dec;191(2):670–679. doi: 10.1016/0042-6822(92)90242-h. [DOI] [PubMed] [Google Scholar]
  5. Barber G. N., Tomita J., Hovanessian A. G., Meurs E., Katze M. G. Functional expression and characterization of the interferon-induced double-stranded RNA activated P68 protein kinase from Escherichia coli. Biochemistry. 1991 Oct 22;30(42):10356–10361. doi: 10.1021/bi00106a038. [DOI] [PubMed] [Google Scholar]
  6. Barber G. N., Wambach M., Wong M. L., Dever T. E., Hinnebusch A. G., Katze M. G. Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4621–4625. doi: 10.1073/pnas.90.10.4621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Beattie E., Tartaglia J., Paoletti E. Vaccinia virus-encoded eIF-2 alpha homolog abrogates the antiviral effect of interferon. Virology. 1991 Jul;183(1):419–422. doi: 10.1016/0042-6822(91)90158-8. [DOI] [PubMed] [Google Scholar]
  8. Behrmann I., Walczak H., Krammer P. H. Structure of the human APO-1 gene. Eur J Immunol. 1994 Dec;24(12):3057–3062. doi: 10.1002/eji.1830241221. [DOI] [PubMed] [Google Scholar]
  9. Bertin J., Armstrong R. C., Ottilie S., Martin D. A., Wang Y., Banks S., Wang G. H., Senkevich T. G., Alnemri E. S., Moss B. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1172–1176. doi: 10.1073/pnas.94.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brand S. R., Kobayashi R., Mathews M. B. The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR. J Biol Chem. 1997 Mar 28;272(13):8388–8395. doi: 10.1074/jbc.272.13.8388. [DOI] [PubMed] [Google Scholar]
  11. Carroll K., Elroy-Stein O., Moss B., Jagus R. Recombinant vaccinia virus K3L gene product prevents activation of double-stranded RNA-dependent, initiation factor 2 alpha-specific protein kinase. J Biol Chem. 1993 Jun 15;268(17):12837–12842. [PubMed] [Google Scholar]
  12. Castelli J. C., Hassel B. A., Wood K. A., Li X. L., Amemiya K., Dalakas M. C., Torrence P. F., Youle R. J. A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system. J Exp Med. 1997 Sep 15;186(6):967–972. doi: 10.1084/jem.186.6.967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chang H. W., Watson J. C., Jacobs B. L. The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4825–4829. doi: 10.1073/pnas.89.11.4825. [DOI] [PMC free article] [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. Choi S. Y., Scherer B. J., Schnier J., Davies M. V., Kaufman R. J., Hershey J. W. Stimulation of protein synthesis in COS cells transfected with variants of the alpha-subunit of initiation factor eIF-2. J Biol Chem. 1992 Jan 5;267(1):286–293. [PubMed] [Google Scholar]
  16. Chong K. L., Feng L., Schappert K., Meurs E., Donahue T. F., Friesen J. D., Hovanessian A. G., Williams B. R. Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2. EMBO J. 1992 Apr;11(4):1553–1562. doi: 10.1002/j.1460-2075.1992.tb05200.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chu K., Niu X., Williams L. T. A Fas-associated protein factor, FAF1, potentiates Fas-mediated apoptosis. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11894–11898. doi: 10.1073/pnas.92.25.11894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Clemens M. J., Elia A. The double-stranded RNA-dependent protein kinase PKR: structure and function. J Interferon Cytokine Res. 1997 Sep;17(9):503–524. doi: 10.1089/jir.1997.17.503. [DOI] [PubMed] [Google Scholar]
  19. Clemens M. J., Laing K. G., Jeffrey I. W., Schofield A., Sharp T. V., Elia A., Matys V., James M. C., Tilleray V. J. Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs. Biochimie. 1994;76(8):770–778. doi: 10.1016/0300-9084(94)90081-7. [DOI] [PubMed] [Google Scholar]
  20. Crook N. E., Clem R. J., Miller L. K. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol. 1993 Apr;67(4):2168–2174. doi: 10.1128/jvi.67.4.2168-2174.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Davies M. V., Chang H. W., Jacobs B. L., Kaufman R. J. The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-dependent protein kinase by different mechanisms. J Virol. 1993 Mar;67(3):1688–1692. doi: 10.1128/jvi.67.3.1688-1692.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Davies M. V., Elroy-Stein O., Jagus R., Moss B., Kaufman R. J. The vaccinia virus K3L gene product potentiates translation by inhibiting double-stranded-RNA-activated protein kinase and phosphorylation of the alpha subunit of eukaryotic initiation factor 2. J Virol. 1992 Apr;66(4):1943–1950. doi: 10.1128/jvi.66.4.1943-1950.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. DeGracia D. J., Sullivan J. M., Neumar R. W., Alousi S. S., Hikade K. R., Pittman J. E., White B. C., Rafols J. A., Krause G. S. Effect of brain ischemia and reperfusion on the localization of phosphorylated eukaryotic initiation factor 2 alpha. J Cereb Blood Flow Metab. 1997 Dec;17(12):1291–1302. doi: 10.1097/00004647-199712000-00004. [DOI] [PubMed] [Google Scholar]
  24. Debbas M., White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993 Apr;7(4):546–554. doi: 10.1101/gad.7.4.546. [DOI] [PubMed] [Google Scholar]
  25. Der S. D., Yang Y. L., Weissmann C., Williams B. R. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3279–3283. doi: 10.1073/pnas.94.7.3279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Dever T. E., Chen J. J., Barber G. N., Cigan A. M., Feng L., Donahue T. F., London I. M., Katze M. G., Hinnebusch A. G. Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4616–4620. doi: 10.1073/pnas.90.10.4616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Dever T. E., Feng L., Wek R. C., Cigan A. M., Donahue T. F., Hinnebusch A. G. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992 Feb 7;68(3):585–596. doi: 10.1016/0092-8674(92)90193-g. [DOI] [PubMed] [Google Scholar]
  28. Donzé O., Jagus R., Koromilas A. E., Hershey J. W., Sonenberg N. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 1995 Aug 1;14(15):3828–3834. doi: 10.1002/j.1460-2075.1995.tb00052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Gale M. J., Jr, Korth M. J., Tang N. M., Tan S. L., Hopkins D. A., Dever T. E., Polyak S. J., Gretch D. R., Katze M. G. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997 Apr 14;230(2):217–227. doi: 10.1006/viro.1997.8493. [DOI] [PubMed] [Google Scholar]
  30. Gossen M., Freundlieb S., Bender G., Müller G., Hillen W., Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science. 1995 Jun 23;268(5218):1766–1769. doi: 10.1126/science.7792603. [DOI] [PubMed] [Google Scholar]
  31. Hakem R., Hakem A., Duncan G. S., Henderson J. T., Woo M., Soengas M. S., Elia A., de la Pompa J. L., Kagi D., Khoo W. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 1998 Aug 7;94(3):339–352. doi: 10.1016/s0092-8674(00)81477-4. [DOI] [PubMed] [Google Scholar]
  32. Harada H., Kitagawa M., Tanaka N., Yamamoto H., Harada K., Ishihara M., Taniguchi T. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993 Feb 12;259(5097):971–974. doi: 10.1126/science.8438157. [DOI] [PubMed] [Google Scholar]
  33. Hershey J. W. Translational control in mammalian cells. Annu Rev Biochem. 1991;60:717–755. doi: 10.1146/annurev.bi.60.070191.003441. [DOI] [PubMed] [Google Scholar]
  34. Hinnebusch A. G. Translational regulation of yeast GCN4. A window on factors that control initiator-trna binding to the ribosome. J Biol Chem. 1997 Aug 29;272(35):21661–21664. doi: 10.1074/jbc.272.35.21661. [DOI] [PubMed] [Google Scholar]
  35. Hsu H., Xiong J., Goeddel D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995 May 19;81(4):495–504. doi: 10.1016/0092-8674(95)90070-5. [DOI] [PubMed] [Google Scholar]
  36. Hu Y., Benedict M. A., Wu D., Inohara N., Núez G. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4386–4391. doi: 10.1073/pnas.95.8.4386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Icely P. L., Gros P., Bergeron J. J., Devault A., Afar D. E., Bell J. C. TIK, a novel serine/threonine kinase, is recognized by antibodies directed against phosphotyrosine. J Biol Chem. 1991 Aug 25;266(24):16073–16077. [PubMed] [Google Scholar]
  38. Ito T., Jagus R., May W. S. Interleukin 3 stimulates protein synthesis by regulating double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7455–7459. doi: 10.1073/pnas.91.16.7455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  40. Kaufman R. J., Davies M. V., Pathak V. K., Hershey J. W. The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs. Mol Cell Biol. 1989 Mar;9(3):946–958. doi: 10.1128/mcb.9.3.946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kaufman R. J., Murtha P., Davies M. V. Translational efficiency of polycistronic mRNAs and their utilization to express heterologous genes in mammalian cells. EMBO J. 1987 Jan;6(1):187–193. doi: 10.1002/j.1460-2075.1987.tb04737.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kayagaki N., Yamaguchi N., Nagao F., Matsuo S., Maeda H., Okumura K., Yagita H. Polymorphism of murine Fas ligand that affects the biological activity. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3914–3919. doi: 10.1073/pnas.94.8.3914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kibler K. V., Shors T., Perkins K. B., Zeman C. C., Banaszak M. P., Biesterfeldt J., Langland J. O., Jacobs B. L. Double-stranded RNA is a trigger for apoptosis in vaccinia virus-infected cells. J Virol. 1997 Mar;71(3):1992–2003. doi: 10.1128/jvi.71.3.1992-2003.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. King P., Goodbourn S. STAT1 is inactivated by a caspase. J Biol Chem. 1998 Apr 10;273(15):8699–8704. doi: 10.1074/jbc.273.15.8699. [DOI] [PubMed] [Google Scholar]
  45. Kluck R. M., Bossy-Wetzel E., Green D. R., Newmeyer D. D. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997 Feb 21;275(5303):1132–1136. doi: 10.1126/science.275.5303.1132. [DOI] [PubMed] [Google Scholar]
  46. Knudson C. M., Korsmeyer S. J. Bcl-2 and Bax function independently to regulate cell death. Nat Genet. 1997 Aug;16(4):358–363. doi: 10.1038/ng0897-358. [DOI] [PubMed] [Google Scholar]
  47. Koopman G., Reutelingsperger C. P., Kuijten G. A., Keehnen R. M., Pals S. T., van Oers M. H. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994 Sep 1;84(5):1415–1420. [PubMed] [Google Scholar]
  48. Koromilas A. E., Roy S., Barber G. N., Katze M. G., Sonenberg N. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science. 1992 Sep 18;257(5077):1685–1689. doi: 10.1126/science.1382315. [DOI] [PubMed] [Google Scholar]
  49. Kuida K., Haydar T. F., Kuan C. Y., Gu Y., Taya C., Karasuyama H., Su M. S., Rakic P., Flavell R. A. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998 Aug 7;94(3):325–337. doi: 10.1016/s0092-8674(00)81476-2. [DOI] [PubMed] [Google Scholar]
  50. Kumar A., Haque J., Lacoste J., Hiscott J., Williams B. R. Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6288–6292. doi: 10.1073/pnas.91.14.6288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kumar A., Yang Y. L., Flati V., Der S., Kadereit S., Deb A., Haque J., Reis L., Weissmann C., Williams B. R. Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-kappaB. EMBO J. 1997 Jan 15;16(2):406–416. doi: 10.1093/emboj/16.2.406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Langland J. O., Pettiford S., Jiang B., Jacobs B. L. Products of the porcine group C rotavirus NSP3 gene bind specifically to double-stranded RNA and inhibit activation of the interferon-induced protein kinase PKR. J Virol. 1994 Jun;68(6):3821–3829. doi: 10.1128/jvi.68.6.3821-3829.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Laurent A. G., Krust B., Galabru J., Svab J., Hovanessian A. G. Monoclonal antibodies to an interferon-induced Mr 68,000 protein and their use for the detection of double-stranded RNA-dependent protein kinase in human cells. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4341–4345. doi: 10.1073/pnas.82.13.4341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Lee S. B., Esteban M. The interferon-induced double-stranded RNA-activated human p68 protein kinase inhibits the replication of vaccinia virus. Virology. 1993 Apr;193(2):1037–1041. doi: 10.1006/viro.1993.1223. [DOI] [PubMed] [Google Scholar]
  55. Lee S. B., Esteban M. The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis. Virology. 1994 Mar;199(2):491–496. doi: 10.1006/viro.1994.1151. [DOI] [PubMed] [Google Scholar]
  56. Lee S. B., Rodríguez D., Rodríguez J. R., Esteban M. The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bcl-2, and involves ICE-like proteases. Virology. 1997 Apr 28;231(1):81–88. doi: 10.1006/viro.1997.8494. [DOI] [PubMed] [Google Scholar]
  57. Lee T. G., Tang N., Thompson S., Miller J., Katze M. G. The 58,000-dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a member of the tetratricopeptide repeat family of proteins. Mol Cell Biol. 1994 Apr;14(4):2331–2342. doi: 10.1128/mcb.14.4.2331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Lengyel P. Tumor-suppressor genes: news about the interferon connection. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5893–5895. doi: 10.1073/pnas.90.13.5893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Levin D., London I. M. Regulation of protein synthesis: activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2. Proc Natl Acad Sci U S A. 1978 Mar;75(3):1121–1125. doi: 10.1073/pnas.75.3.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Li P., Nijhawan D., Budihardjo I., Srinivasula S. M., Ahmad M., Alnemri E. S., Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479–489. doi: 10.1016/s0092-8674(00)80434-1. [DOI] [PubMed] [Google Scholar]
  61. Liu X., Kim C. N., Yang J., Jemmerson R., Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996 Jul 12;86(1):147–157. doi: 10.1016/s0092-8674(00)80085-9. [DOI] [PubMed] [Google Scholar]
  62. Luo X., Budihardjo I., Zou H., Slaughter C., Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 1998 Aug 21;94(4):481–490. doi: 10.1016/s0092-8674(00)81589-5. [DOI] [PubMed] [Google Scholar]
  63. MacFarlane M., Ahmad M., Srinivasula S. M., Fernandes-Alnemri T., Cohen G. M., Alnemri E. S. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997 Oct 10;272(41):25417–25420. doi: 10.1074/jbc.272.41.25417. [DOI] [PubMed] [Google Scholar]
  64. Manche L., Green S. R., Schmedt C., Mathews M. B. Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol Cell Biol. 1992 Nov;12(11):5238–5248. doi: 10.1128/mcb.12.11.5238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Manon S., Chaudhuri B., Guérin M. Release of cytochrome c and decrease of cytochrome c oxidase in Bax-expressing yeast cells, and prevention of these effects by coexpression of Bcl-xL. FEBS Lett. 1997 Sep 22;415(1):29–32. doi: 10.1016/s0014-5793(97)01087-9. [DOI] [PubMed] [Google Scholar]
  66. Martin S. J., Green D. R. Protease activation during apoptosis: death by a thousand cuts? Cell. 1995 Aug 11;82(3):349–352. doi: 10.1016/0092-8674(95)90422-0. [DOI] [PubMed] [Google Scholar]
  67. Mathews M. B., Shenk T. Adenovirus virus-associated RNA and translation control. J Virol. 1991 Nov;65(11):5657–5662. doi: 10.1128/jvi.65.11.5657-5662.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. McMillan N. A., Chun R. F., Siderovski D. P., Galabru J., Toone W. M., Samuel C. E., Mak T. W., Hovanessian A. G., Jeang K. T., Williams B. R. HIV-1 Tat directly interacts with the interferon-induced, double-stranded RNA-dependent kinase, PKR. Virology. 1995 Nov 10;213(2):413–424. doi: 10.1006/viro.1995.0014. [DOI] [PubMed] [Google Scholar]
  69. Meurs E. F., Galabru J., Barber G. N., Katze M. G., Hovanessian A. G. Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):232–236. doi: 10.1073/pnas.90.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Meurs E., Chong K., Galabru J., Thomas N. S., Kerr I. M., Williams B. R., Hovanessian A. G. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990 Jul 27;62(2):379–390. doi: 10.1016/0092-8674(90)90374-n. [DOI] [PubMed] [Google Scholar]
  71. Miller J. E., Samuel C. E. Proteolytic cleavage of the reovirus sigma 3 protein results in enhanced double-stranded RNA-binding activity: identification of a repeated basic amino acid motif within the C-terminal binding region. J Virol. 1992 Sep;66(9):5347–5356. doi: 10.1128/jvi.66.9.5347-5356.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Morris D. R. Growth control of translation in mammalian cells. Prog Nucleic Acid Res Mol Biol. 1995;51:339–363. doi: 10.1016/s0079-6603(08)60883-1. [DOI] [PubMed] [Google Scholar]
  73. Mundschau L. J., Faller D. V. Platelet-derived growth factor signal transduction through the interferon-inducible kinase PKR. Immediate early gene induction. J Biol Chem. 1995 Feb 17;270(7):3100–3106. doi: 10.1074/jbc.270.7.3100. [DOI] [PubMed] [Google Scholar]
  74. 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]
  75. Muzio M., Stockwell B. R., Stennicke H. R., Salvesen G. S., Dixit V. M. An induced proximity model for caspase-8 activation. J Biol Chem. 1998 Jan 30;273(5):2926–2930. doi: 10.1074/jbc.273.5.2926. [DOI] [PubMed] [Google Scholar]
  76. Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. doi: 10.1016/s0092-8674(00)81874-7. [DOI] [PubMed] [Google Scholar]
  77. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  78. Pan G., O'Rourke K., Dixit V. M. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem. 1998 Mar 6;273(10):5841–5845. doi: 10.1074/jbc.273.10.5841. [DOI] [PubMed] [Google Scholar]
  79. Panniers R., Henshaw E. C. A GDP/GTP exchange factor essential for eukaryotic initiation factor 2 cycling in Ehrlich ascites tumor cells and its regulation by eukaryotic initiation factor 2 phosphorylation. J Biol Chem. 1983 Jul 10;258(13):7928–7934. [PubMed] [Google Scholar]
  80. Pastorino J. G., Chen S. T., Tafani M., Snyder J. W., Farber J. L. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem. 1998 Mar 27;273(13):7770–7775. doi: 10.1074/jbc.273.13.7770. [DOI] [PubMed] [Google Scholar]
  81. Reed J. C. Cytochrome c: can't live with it--can't live without it. Cell. 1997 Nov 28;91(5):559–562. doi: 10.1016/s0092-8674(00)80442-0. [DOI] [PubMed] [Google Scholar]
  82. Reed J. C. Double identity for proteins of the Bcl-2 family. Nature. 1997 Jun 19;387(6635):773–776. doi: 10.1038/42867. [DOI] [PubMed] [Google Scholar]
  83. Romano P. R., Green S. R., Barber G. N., Mathews M. B., Hinnebusch A. G. Structural requirements for double-stranded RNA binding, dimerization, and activation of the human eIF-2 alpha kinase DAI in Saccharomyces cerevisiae. Mol Cell Biol. 1995 Jan;15(1):365–378. doi: 10.1128/mcb.15.1.365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Roy S., Katze M. G., Parkin N. T., Edery I., Hovanessian A. G., Sonenberg N. Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product. Science. 1990 Mar 9;247(4947):1216–1219. doi: 10.1126/science.2180064. [DOI] [PubMed] [Google Scholar]
  85. Salvesen G. S., Dixit V. M. Caspases: intracellular signaling by proteolysis. Cell. 1997 Nov 14;91(4):443–446. doi: 10.1016/s0092-8674(00)80430-4. [DOI] [PubMed] [Google Scholar]
  86. Samuel C. E. Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology. 1991 Jul;183(1):1–11. doi: 10.1016/0042-6822(91)90112-o. [DOI] [PubMed] [Google Scholar]
  87. Scaffidi C., Fulda S., Srinivasan A., Friesen C., Li F., Tomaselli K. J., Debatin K. M., Krammer P. H., Peter M. E. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998 Mar 16;17(6):1675–1687. doi: 10.1093/emboj/17.6.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Seliger L. S., Giantini M., Shatkin A. J. Translational effects and sequence comparisons of the three serotypes of the reovirus S4 gene. Virology. 1992 Mar;187(1):202–210. doi: 10.1016/0042-6822(92)90308-c. [DOI] [PubMed] [Google Scholar]
  89. Sen G. C., Ransohoff R. M. Interferon-induced antiviral actions and their regulation. Adv Virus Res. 1993;42:57–102. doi: 10.1016/s0065-3527(08)60083-4. [DOI] [PubMed] [Google Scholar]
  90. Sonenberg N. mRNA translation: influence of the 5' and 3' untranslated regions. Curr Opin Genet Dev. 1994 Apr;4(2):310–315. doi: 10.1016/s0959-437x(05)80059-0. [DOI] [PubMed] [Google Scholar]
  91. Srinivasula S. M., Ahmad M., Fernandes-Alnemri T., Alnemri E. S. Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell. 1998 Jun;1(7):949–957. doi: 10.1016/s1097-2765(00)80095-7. [DOI] [PubMed] [Google Scholar]
  92. Srivastava S. P., Kumar K. U., Kaufman R. J. Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem. 1998 Jan 23;273(4):2416–2423. doi: 10.1074/jbc.273.4.2416. [DOI] [PubMed] [Google Scholar]
  93. St Johnston D., Brown N. H., Gall J. G., Jantsch M. A conserved double-stranded RNA-binding domain. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10979–10983. doi: 10.1073/pnas.89.22.10979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Su T. Z., Wang M., Oxender D. L., Saltiel A. R. Troglitazone increases system A amino acid transport in 3T3-L1 cells. Endocrinology. 1998 Mar;139(3):832–837. doi: 10.1210/endo.139.3.5795. [DOI] [PubMed] [Google Scholar]
  95. Takizawa T., Ohashi K., Nakanishi Y. Possible involvement of double-stranded RNA-activated protein kinase in cell death by influenza virus infection. J Virol. 1996 Nov;70(11):8128–8132. doi: 10.1128/jvi.70.11.8128-8132.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Teodoro J. G., Branton P. E. Regulation of apoptosis by viral gene products. J Virol. 1997 Mar;71(3):1739–1746. doi: 10.1128/jvi.71.3.1739-1746.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Tewari M., Dixit V. M. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem. 1995 Feb 17;270(7):3255–3260. doi: 10.1074/jbc.270.7.3255. [DOI] [PubMed] [Google Scholar]
  98. Thome M., Schneider P., Hofmann K., Fickenscher H., Meinl E., Neipel F., Mattmann C., Burns K., Bodmer J. L., Schröter M. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997 Apr 3;386(6624):517–521. doi: 10.1038/386517a0. [DOI] [PubMed] [Google Scholar]
  99. Thomis D. C., Samuel C. E. Mechanism of interferon action: autoregulation of RNA-dependent P1/eIF-2 alpha protein kinase (PKR) expression in transfected mammalian cells. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10837–10841. doi: 10.1073/pnas.89.22.10837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Thomis D. C., Samuel C. E. Mechanism of interferon action: evidence for intermolecular autophosphorylation and autoactivation of the interferon-induced, RNA-dependent protein kinase PKR. J Virol. 1993 Dec;67(12):7695–7700. doi: 10.1128/jvi.67.12.7695-7700.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Vander Heiden M. G., Chandel N. S., Williamson E. K., Schumacker P. T., Thompson C. B. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell. 1997 Nov 28;91(5):627–637. doi: 10.1016/s0092-8674(00)80450-x. [DOI] [PubMed] [Google Scholar]
  102. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  103. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
  104. Wong A. H., Tam N. W., Yang Y. L., Cuddihy A. R., Li S., Kirchhoff S., Hauser H., Decker T., Koromilas A. E. Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways. EMBO J. 1997 Mar 17;16(6):1291–1304. doi: 10.1093/emboj/16.6.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Yang J., Liu X., Bhalla K., Kim C. N., Ibrado A. M., Cai J., Peng T. I., Jones D. P., Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997 Feb 21;275(5303):1129–1132. doi: 10.1126/science.275.5303.1129. [DOI] [PubMed] [Google Scholar]
  106. Yang Y. L., Reis L. F., Pavlovic J., Aguzzi A., Schäfer R., Kumar A., Williams B. R., Aguet M., Weissmann C. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 1995 Dec 15;14(24):6095–6106. doi: 10.1002/j.1460-2075.1995.tb00300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Yeh W. C., de la Pompa J. L., McCurrach M. E., Shu H. B., Elia A. J., Shahinian A., Ng M., Wakeham A., Khoo W., Mitchell K. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 1998 Mar 20;279(5358):1954–1958. doi: 10.1126/science.279.5358.1954. [DOI] [PubMed] [Google Scholar]
  108. Yeung M. C., Liu J., Lau A. S. An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor-induced apoptosis in U937 cells. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12451–12455. doi: 10.1073/pnas.93.22.12451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Zhou A., Paranjape J., Brown T. L., Nie H., Naik S., Dong B., Chang A., Trapp B., Fairchild R., Colmenares C. Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L. EMBO J. 1997 Nov 3;16(21):6355–6363. doi: 10.1093/emboj/16.21.6355. [DOI] [PMC free article] [PubMed] [Google Scholar]