Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

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Abstract

Oncogenic virus proteins often target to tumor suppressor p53 during virus life cycle. In the case of hepatitis C virus (HCV) core protein, it has been shown to affect p53-dependent transcription. Here, we further characterized the in vitro and in vivo interactions between HCV core protein and p53 and showed that these two proteins colocalized in subnuclear granular structures and the perinuclear area. By use of a reporter assay, we observed that while low level of HCV core protein enhanced the transactivational activity of p53, high level of HCV core protein inhibited this activity. In both cases, however, HCV core protein increased the p53 DNA-binding affinity in gel retardation analyses, likely due to the hyperacetylation of p53 Lys373 and Lys382 residues. Additionally, HCV core protein, depending on its expression level, had differential effects on the Ser15 phosphorylation of p53. Moreover, HCV core protein could rescue p53-mediated suppressive effects on both RNA polymerase I and III transcriptions. Collectively, our results indicate that HCV core protein targets to p53 pathway via at least three means: physical interaction, modulation of p53 gene regulatory activity and post-translational modification. This feature of HCV core protein, may potentially contribute to the HCV-associated pathogenesis.

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Acknowledgements

We thank Dr LH Hwang for generously providing HepG2 cells that constitutively express HCV core protein. We also thank Dr L Comai for prHu3-CAT, Dr DL Johnson for pArgMaxi, and Dr YS Lin for pCEP4-p53 variants. This work was supported by the following grants to YHW Lee: NHRI-EX90-9002BL, NHRI-EX91-9002BL, and NHRI-EX92-9002BL from the National Health Research Institute, and in part by Grants NSC89-2320-B-010-141, NSC90-2320-B-010-083, and NSC91-2320-B-010-072 from the National Science Council.

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Correspondence to Yan-Hwa Wu Lee.

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Keywords

  • HCV
  • core protein
  • p53
  • post-translational modification

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