Abstract
The tumor suppressor p53 is a multifunctional protein that plays a critical role in modulating cellular responses upon DNA damage or other stresses. These functions of p53 are regulated both by protein-protein interactions and phosphorylation. The double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2α. PKR is an interferon (IFN)-inducible protein that is thought to mediate the anti-viral and anti-proliferative effects of IFN via its capacity to inhibit protein synthesis. Here we report that PKR physically associates with p53. The interaction of PKR with p53 is enhanced by IFNs and upon conditions that p53 acquires a wild type conformation. PKR/p53 complex formation in vitro requires the N-terminal regulatory domain of PKR and the last 30 amino acids of the C-terminus of human p53. In addition, p53 may function as a substrate of PKR since phosphorylation of human p53 on serine392 is induced by activated PKR in vitro. These novel findings raise the possibility of a functional interaction between PKR and p53 in vivo, which may account, at least in part, for the ability of each protein to regulate gene expression at both the transcriptional and the translational levels.
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Acknowledgements
We thank Y-L Yang and C Weissmann for PKR+/+ and PKR−/− MEFs; GN Barber and A Darveau for anti-human PKR (13B8-F9) monoclonal antibody; J Bell for anti-mouse PKR (TIK) antibodies; A Levine for human wild type p53 cDNA; T Shenk for the GST-p53 fusion proteins; E White for BRK cells expressing the ts mutant p53 (val135) and E1A and E1B genes; C Proud for purified eIF-2α; MG Katze for PKRK296R cDNA; Y Taya for anti-phosphoserine389 p53 specific antibody and R Wek for the histidine-tagged eIF-2α constructs. Supported by research grants from the National Cancer Institute of Canada, Medical Research Council of Canada and The Cancer Research Society Inc to AEK. ARC is the recipient of a studentship from The Cancer Research Society Inc., AH-TW is supported by a Terry Fox Research Studentship from the National Cancer Institute of Canada and NWNT by a Doctoral Research Award from the Medical Research Council of Canada. AEK is a member of the Terry Fox Group in Molecular Oncology and a recipient of an MRC Scientist Award.
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Cuddihy, A., Hoi-Tao Wong, A., Wai Ning Tam, N. et al. The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18, 2690–2702 (1999). https://doi.org/10.1038/sj.onc.1202620
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DOI: https://doi.org/10.1038/sj.onc.1202620
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