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Inhibition of double-stranded RNA- and tumor necrosis factor alpha-mediated apoptosis by tetratricopeptide repeat protein and cochaperone P58(IPK).
Title | Inhibition of double-stranded RNA- and tumor necrosis factor alpha-mediated apoptosis by tetratricopeptide repeat protein and cochaperone P58(IPK). |
Publication Type | Journal Article |
Year of Publication | 1999 |
Authors | Tang, NM, Korth, MJ, Gale, M, Wambach, M, Der, SD, Bandyopadhyay, SK, Williams, BR, Katze, MG |
Journal | Mol Cell Biol |
Volume | 19 |
Issue | 7 |
Pagination | 4757-65 |
Date Published | 1999 Jul |
ISSN | 0270-7306 |
Keywords | 3T3 Cells, Animals, Apoptosis, eIF-2 Kinase, Eukaryotic Initiation Factor-2, HSP40 Heat-Shock Proteins, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Chaperones, Mutagenesis, NF-kappa B, Phenotype, Phosphorylation, Poly I-C, Protein Kinase Inhibitors, Rabbits, Repressor Proteins, RNA, Double-Stranded, Transformation, Genetic, Tumor Necrosis Factor-alpha |
Abstract | P58(IPK) 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 P58(IPK), we generated NIH 3T3 cell lines expressing either wild-type P58(IPK) or a P58(IPK) deletion mutant, DeltaTPR6, that does not bind to or inhibit PKR. When treated with double-stranded RNA (dsRNA), DeltaTPR6-expressing cells exhibited a significant increase in eukaryotic initiation factor 2alpha phosphorylation and NF-kappaB activation, indicating a functional PKR. In contrast, both of these PKR-dependent events were blocked by the overexpression of wild-type P58(IPK). In addition, the P58(IPK) cell line, but not the DeltaTPR6 cell line, was resistant to dsRNA-induced apoptosis. Together, these findings demonstrate that P58(IPK) regulates dsRNA signaling pathways by inhibiting multiple PKR-dependent functions. In contrast, both the P58(IPK) and DeltaTPR6 cell lines were resistant to tumor necrosis factor alpha-induced apoptosis, suggesting that P58(IPK) 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 DeltaTPR6-expressing cells, the DeltaTPR6 cell line displayed a transformed phenotype and was tumorigenic in nude mice. Thus, the antiapoptotic function of P58(IPK) may be an important factor in its ability to malignantly transform cells. |
Alternate Journal | Mol. Cell. Biol. |
PubMed ID | 10373525 |