Inhibition of Double-Stranded RNA- and Tumor Necrosis Factor Alpha-Mediated Apoptosis by Tetratricopeptide Repeat Protein and Cochaperone P58IPK
AUTOR(ES)
Tang, Norina M.
FONTE
American Society for Microbiology
RESUMO
P58IPK is a tetratricopeptide repeat-containing cochaperone that is involved in stress-activated cellular pathways and that inhibits the activity of protein kinase PKR, a primary mediator of the antiviral and antiproliferative properties of interferon. To gain better insight into the molecular actions of P58IPK, we generated NIH 3T3 cell lines expressing either wild-type P58IPK or a P58IPK deletion mutant, ΔTPR6, that does not bind to or inhibit PKR. When treated with double-stranded RNA (dsRNA), ΔTPR6-expressing cells exhibited a significant increase in eukaryotic initiation factor 2α phosphorylation and NF-κB activation, indicating a functional PKR. In contrast, both of these PKR-dependent events were blocked by the overexpression of wild-type P58IPK. In addition, the P58IPK cell line, but not the ΔTPR6 cell line, was resistant to dsRNA-induced apoptosis. Together, these findings demonstrate that P58IPK regulates dsRNA signaling pathways by inhibiting multiple PKR-dependent functions. In contrast, both the P58IPK and ΔTPR6 cell lines were resistant to tumor necrosis factor alpha-induced apoptosis, suggesting that P58IPK may function as a more general suppressor of programmed cell death independently of its PKR-inhibitory properties. In accordance with this hypothesis, although PKR remained active in ΔTPR6-expressing cells, the ΔTPR6 cell line displayed a transformed phenotype and was tumorigenic in nude mice. Thus, the antiapoptotic function of P58IPK may be an important factor in its ability to malignantly transform cells.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=84274Documentos Relacionados
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