Protein kinase interferon-induced

Desbarats J, Wade T, Wade WF, Newell MK (1999) Dichotomy between naive and memory CD4( + ) T cell responses to Fas engagement. Proc Natl Acad Sci USA 96 8104-8109 Dimitrov T, Krajcsi P, Hermiston TW, Tollefson AE, Hannink M, Wold WS (1997) Adenovirus E3-10.4K/14.5K protein complex inhibits tumor necrosis factor-induced translocation of cytosolic phospholipase A2 to membranes. J Virol 71 2830-2837 Donze O, Dostie J, Sonenberg N (1999) Regulatable expression of the interferon-induced double-stranded RNA dependent protein kinase PKR induces apoptosis and Fas receptor expression. Virology 256 322-329... 

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

The ability of interferons (especially type I interferons) to induce an antiviral state is unlikely to be solely dependent upon the enzymatic mechanisms discussed above. Furthermore the 2 -5 A synthetase and eIF-2a kinase systems may play important roles in mediating additional interferon actions. The ability of such systems to stall protein synthesis in cells may play a role in interferon-induced alterations of cellular differentiation or cell cycle progression. They may also be involved in mediating interferon-induced anti-proliferative effects on various transformed cells. 

Interferons are cellular glycoproteins produced by the host cells which exert complex antiviral, immunoregulatory and antiproliferative activities. After binding to interferon receptors it acts through cellular metabolic processes which involves synthesis of viral RNA and proteins. Interferon receptors are tyrosine protein kinase receptors which on activation phosphorylate cellular proteins. These then induce transcription of interferon induced proteins which exert antiviral effects. There are three type of interferons - alpha, beta and gamma. 

Fig. 1.56. Control of eIF-2 by phosphorylation. Phosphorylated eIF-2 GDP binds strongly to eIF-2B without nucleotide exchange occurring. Initiation of protein biosynthesis is not possible in this case.In reticulocytes, eIF-2 is subject to phosphorylation by the heme-regulated eIF-2-kinase (HRI). The activity of the dimeric HRI is regulated via the heme concentration. Another protein kinase that can phosphorylate and regulate eIF-2 is the RNA-dependent eIF2a-kinase (PKR). The latter is induced by interferons and activated by double stranded RNA.

This is converted to an inactive phosphorylated form by a dsRNA-dependent protein kinase205 (Fig. 31-10). The protein kinase also appears to be an interferon-induced protein206 as is the oligo(2 -5 A)-activated RNAse indicated in Fig. 31-10.207 Interferons have effects other than inducing the antiviral state. Thus, human IFN-(32 is identical to a B-cell differentiation factor.208 Both IFN-a and IFN-(3 have antigrowth activity and are currently in use for treatment of some forms of cancer as well as for viral infections.209... 

Binding of human interferon-lb to specific cell receptors induces the expression of a number of interferon-induced gene products (e.g., 2, 5 -oligoandenylate synthetase, protein kinase, and indoleamine 2,3-dioxygenase that are believed to be mediators of the biological actions... 

D. M. Rose, B. W. Winston, E. D. Chan, D. W. H. Riches, and P. M. Henson, Interferon-y and Transforming Growth Factor-P Modulate the Activation of Mitogen-Activated Protein Kinases and Tumor Necrosis Factor-a Production Induced by Fcg-Receptor Stimulation in Murine Macrophages, Biochemical Biophysical Research Communication, 238 (1997) 256-260. 

Although it is not possible to delineate the mechanisms by which interferon beta-lb exerts its activity in MS. it is known that the interferon binds to specific receptors on cell surfaces and induces the expression of a number of interferon-induced gene products, such as 2. 5 -oligoadenylate synthetase and protein kinase. Additionally, interferon beta-lb blocks the synthesis of INF-y. which is believed to be involved in MS attacks. 

Aronica SM, Mantel C, Gonin R, et al. Interferon-inducible protein 10 and macrophage inflammatory protein-1 alpha inhibit growth factor stimulation of Raf-1 kinase activity and protein synthesis in a human growth factor-dependent hematopoietic cell line. J Biol Chem 1995 270 21998-2007. 

The physiological role of dihydrouridine, and, therefore, DUS, remains unknown, but it occurs throughout biology. Human DUS2 is upregulated in pulmonary carcinogenesis and inhibits the kinase activity of PKR, an interferon-induced protein kinase involved in the regulation of antiviral innate immunity. ... 

Mechanisms Interferons are glycoproteins produced in human leukocytes (IFN-a), fibroblasts (IFN-(3), and immune cells (IFN-y)- They exert multiple actions that affect viral RNA and DNA synthesis. Interferons induce the formation of enzymes, including a protein kinase that phosphorylates a factor which blocks peptide chain initiation, a phosphodiesterase that degrades terminal nucleotides of tRNA. and enzymes that activate RNase. 

Meurs EF, Galabru J, Barber GN, Zatze MG, Hovanessian AG (1992) Tumor suppressor function of the interferon-induced double stranded RNA-activated protein kinase. Proc Natl Acad Sci USA 90 ... 

He B, Gross M, Roizman B (1997) The gamma(l)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1 alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci USA 94 843-848 Hollander MC, Zhan Q, Bae I, Fornace AJ, Jr (1997) Mammalian GADD34, an apoptosis- and DNA damage-inducible gene. J Biol Chem 272 13731-13737 Isaacs A, Lindenmann J (1957) Virus interference. I. The interferon. Proceedings of the Royal Society of London 147 258-267... 

Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62 379-390... 

Gil J, Esteban M (2000) The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-ot receptors. Oncogene 19 3665-3674... 

Kitajewski J, Schneider R, Safer B, Munemitsu S, Samuel C, Thimmappaya B, Shenk T (1986) Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell 45 195-200 Korner H, Burgert H-G (1994) Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J Virol 68 1442-1448 Korner H, Fritzsche U, Burgert H-G (1992) Tumor necrosis factor alpha stimulates expression of adenovirus early region 3 proteins implications for viral persistence. Proc Natl Acad Sci USA 89 11857-11861... 

Patel RC, Sen GC. PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J 1998 17(15) 4379-4390. 

Langland JO, Pettifotd S, Jiang B et al. 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 68 6) 3821-3829. 

Sharp TV, Schwemmle M, Jeffrey I et al. Comparative analysis of the regulation of the interferon-inducible protein kinase PKR by Epstein-Barr virus RNAs EBER-1 and EBER-2 and adenovirus VAI RNA. Nucleic Acids Res 1993 21(19) 4483-4490. 

Tan SL, Gale MJ Jr, Katzc MG. Double-stranded RNA-independent dimerization of interferon-induced protein kinase PKR and inhibition of dimerization by the cellular P58IPK inhibitor. Mol Cell Biol 1998 18(5) 2431-2443. 

Taylor DR, Shi ST, Romano PR et al. Inhibition of the interferon-inducible protein kinase PKR by HCVE2 protein. Science 1999 285(5424) 107-110. 

Lee TG, Tomita J, Hovanessian AG et al. Characterization and regulation of the 58,000-dalton cellular inhibitor of the interferon-induced, dsRNA-activated protein kinase. J Biol Chem 1992 267(20) 14238-14243. 

Black TL, Barber GN, Katze MG. Degradation of the interferon-induced 68,000-M(r) protein kinase by poliovirus requires RNA. J Virol 1993 67(2) 79T800. 

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