Cited by 632Open Access
University of California, Irvine
Publishes on Acute Myeloid Leukemia Research, Acute Lymphoblastic Leukemia research, RNA modifications and cancer. 44 papers and 1.5k citations.
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The induction of interferon (IFN) genes by viruses or double-stranded RNA (dsRNA) requires the assembly of a complex set of transcription factors on responsive DNA elements of IFN gene promoters. One of the factors necessary for regulating IFN-beta gene transcription is nuclear factor NF-kappa B, the activation of which is triggered by dsRNA. It has previously been suggested that the dsRNA-activated p68 protein kinase (PKR) may act as an inducer-receptor, transducing the signal from dsRNA to NF-kappa B through phosphorylation of the inhibitor I kappa B. We present direct evidence that PKR can phosphorylate I kappa B-alpha (MAD-3) and activate NF-kappa B DNA binding activity in vitro. We further show that dsRNA induces an unusual phosphorylated form of I kappa B-alpha. The expression of a transdominant mutant PKR is able to perturb the dsRNA-mediated signaling pathway in vivo, suggesting a role for this kinase in IFN-beta gene induction.
The double-stranded RNA (dsRNA)-binding domain of the human p68 kinase has been localized to the N-terminal half of the enzyme by using progressive deletion analysis and in vitro binding assays. To further define the domains responsible for binding to dsRNA, we cloned the mouse dsRNA-activated p65 kinase and used sequence alignment to identify conserved domains in the N-terminal region. Deletions in either of two 12-amino-acid-long and arginine- or lysine-rich regions abrogated binding to dsRNA. Moreover, in an in vivo growth inhibition assay in the yeast Saccharomyces cerevisiae, these mutants failed to exhibit a slow-growth phenotype.
The need for early antimicrobial therapy is well established for life-threatening bacterial and fungal infections including meningitis and sepsis/septic shock. However, a link between the outcome of serious viral infections and delays in antiviral therapy is not as well recognized. Recently, with the occurrence of the influenza A/H1N1 pandemic of 2009, a large body of data regarding this issue has become available. Studies analysing data from this pandemic have consistently shown that delays in initiation of antiviral therapy following symptom onset are significantly associated with disease severity and death. Optimal survival and minimal disease severity appear to result when antivirals are started as soon as possible after symptom onset.