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RNA-dependent Protein Kinase (rna-dependent + protein_kinase)
Selected AbstractsThe lack of RNA-dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infectionIMMUNOLOGY, Issue 4 2006Daniel J. J. Carr Summary Mice deficient in RNA-dependent protein kinase (PKR,/,) or deficient in PKR and a functional 2,,5,-oligoadenylate synthetase (OAS) pathway (PKR/RL,/,) are more susceptible to genital herpes simplex virus type 2 (HSV-2) infection than wild-type mice or mice that are deficient only in a functional OAS pathway (RL,/,) as measured by survival over 30 days. The increase in susceptibility correlated with an increase in virus titre recovered from vaginal tissue or brainstem of infected mice during acute infection. There was also an increase in CD45+ cells and CD8+ T cells residing in the central nervous system of HSV-2-infected PKR/RL,/, mice in comparison with RL,/, or wild-type control animals. In contrast, there was a reduction in the HSV-specific CD8+ T cells within the draining lymph node of the PKR/RL,/, mice. Collectively, activation of PKR, but not of OAS, contributes significantly to the local control and spread of HSV-2 following genital infection. [source] PKR, a cognitive decline biomarker, can regulate translation via two consecutive molecular targets p53 and Redd1 in lymphocytes of AD patientsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Milena Damjanac Abstract In Alzheimer's disease (AD), the control of translation is dysregulated, precisely, two opposite pathways: double-stranded RNA-dependent protein kinase (PKR) is up-regulated and mammalian target of rapamycin (mTOR) is down-regulated. These biochemical alterations were found at the periphery in lymphocytes of AD patients and were significantly correlated with cognitive and memory test scores. However, the molecular crosslink between these two opposite signalling pathways remains unknown. The tumour suppressor p53 and Redd1 (regulated in development and DNA damage response) could be two downstream targets of active PKR to explain the breakdown of translation in AD patients. In this study, the protein and gene levels of p53 and Redd1 were assayed in lymphocytes of AD patients and in age-matched controls by Western blotting and RT-PCR. Furthermore, correlations were analysed with both the level of active PKR and the Mini Mental State Examination score (MMSE). The results show that the gene and protein levels of p53 and Redd1 were significantly increased about 1.5-fold for both gene and Redd1 protein and 2.3-fold for active p53 in AD lymphocytes compared to age-matched controls. Furthermore, statistical correlations between proteins and genes suggest that active PKR could phosphorylate p53 which could induce the transcription of Redd1 gene. No correlations were found between MMSE scores and levels of p53 or Redd1, contrary to active PKR levels. PKR represents a cognitive decline biomarker able to dysregulate translation via two consecutive targets p53 and Redd1 in AD lymphocytes. [source] 2-methoxyestradiol-induced cell death in osteosarcoma cells is preceded by cell cycle arrestJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2008Avudaiappan Maran Abstract 2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17,-Estradiol (E2), induces cell death in osteosarcoma cells. To further understand the molecular mechanisms of action, we have investigated cell cycle progression in 2-ME-treated human osteosarcoma (MG63, SaOS-2 and LM8) cells. At 5 µM, 2-ME induced growth arrest by inducing a block in cell cycle; 2-ME-treatment resulted in 2-fold increases in G1 phase cells and a decrease in S phase cells in MG63 and SaOS-2 osteosarcoma cell lines, compared to the appropriate vehicle controls. 2-ME-treatment induced a threefold increase in the G2 phase in LM8 osteosarcoma cells. The results demonstrated steroid specificity, as the tumorigenic metabolite, 16,-hydroxyestradiol (16-OHE), did not have any effect on cell cycle progression in osteosarcoma cells. The cell cycle arrest coincided with an increase in expression of the cell cycle markers p21, p27 and p53 proteins in 2-ME-treated osteosarcoma cells. Also, MG63 cells, transiently transfected with cDNA for a ,loss of function mutant' RNA-dependent protein kinase (PKR) protein, were resistant to 2-ME-induced cell cycle arrest. These results suggest that 2-ME works in concert with factors regulating cell cycle progression, and cell cycle arrest precedes cell death in 2-ME-treated osteosarcoma cells. J. Cell. Biochem. 104: 1937,1945, 2008. © 2008 Wiley-Liss, Inc. [source] Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirinJOURNAL OF VIRAL HEPATITIS, Issue 2 2003C.-H. Hung summary. Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV-1b patients who had received IFN- ,2b (3 or 5 MU three times weekly) and ribavirin (800,1200 mg per day) for 24 weeks. The amino acid sequences of the NS5A and PKR-eIF2, phosphorylation homology domain (E2-PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A,PKR binding domain (2209,2274), interferon sensitivity-determining region (ISDR) (2209,2248), and E2-PePHD sequence (659,670) in patients with and without SVR were 4.53 ± 3.31 vs 2.83 ± 1.78 (P = 0.094), 2.45 ± 2.74 vs 1.03 ± 1.32 (P = 0.042) and 0.25 ± 0.70 vs 0.03 ± 0.17 (P = 0.109), respectively. Patients with a mutant-type (, 4) NS5A,ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A,ISDR (, 4 vs < 4) was the only independent variable of treatment outcome. Our study showed that NS5A,ISDR mutations were correlated with the SVR to combination therapy in chronic HCV-1b patients in Taiwan. [source] Site-Specific Modification of Epstein,Barr Virus-Encoded RNA 1 with N2 -Benzylguanosine Limits the Binding Sites Occupied by PKRCHEMBIOCHEM, Issue 3 2004Sujiet Puthenveetil Examining viral decoys: Epstein,Barr virus (EBV) generates small RNA inhibitors of the human RNA-dependent protein kinase (PKR). We demonstrate that chemical synthesis of analogues of the EBV PKR inhibitor EBER1 bearing single N2 -benzylguanosine substitutions (BnG6 or BnG29) can be used to control the way PKR binds this RNA. [source] | ||||||||||