Abnormal levels and minimal activity of the dsRNA-activated protein kinase, PKR, in breast carcinoma cells.
The interferon induced, dsRNA-activated, protein kinase, PKR, is a key regulator of translational initiation, playing an important role in the regulation of cell proliferation, apoptosis and transformation. PKR levels correlate inversely with proliferative activity in several human tumor systems. This inverse relationship breaks down in human invasive ductal breast carcinomas which exhibit high levels of PKR (Haines et al., Tumor Biol. 17 (1996) 5-12). Consistent with the data from human tumors, the levels of PKR in several breast carcinoma cell lines, MCF7, T47D, BT20, MDAMB231 and MDAMB468, are paradoxically high compared to those found in the normal breast cell lines MCF10A and Hs578Bst. The activity of affinity- or immuno-purified PKR from MCF7, T47D, and BT20 cells appears to be severely attenuated, as judged by its ability to autophosphorylate, or phosphorylate eIF2 alpha. Furthermore, the activity of the kinase from breast carcinoma cells is refractory to stimulation by dsRNA or heparin. However, PKR from breast carcinoma cells remains functional with respect to its ability to bind dsRNA. The activity of PKR from MCF10A cells is reduced by prior incubation with extracts from MCF7 cells, suggesting that MCF7 extracts contain a transdominant inhibitor of PKR. Deregulation of PKR may therefore provide a mechanism for the development or maintenance of a transformed phenotype of human breast carcinomas, mimicking the effects of manipulation of PKR or eIF2 activity observed in experimental systems. Thus, breast carcinomas may provide the first indication of a role for PKR in the pathogenesis of a naturally occurring human cancer.
Savinova
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O
Center of Marine Biotechnology, University of Maryland Biotechnology Institute, Baltimore, USA.
Joshi
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B
Jagus
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R
D001940:Breast / Q000201:enzymology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002457:Cell Extracts / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D010766:Phosphorylation; D011066:Poly C / Q000494:pharmacology; D011069:Poly I / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000187:drug effects / Q000378:metabolism*
D002457:Cell Extracts; D015852:Eukaryotic Initiation Factor-2; D011069:Poly I; D011066:Poly C; D016899:Interferon-beta; D006493:Heparin; D019892:eIF-2 Kinase