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| Subject Categories: Chromatin & Transcription |
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| The EMBO Journal
(2004) 23, 2269–2280, doi:10.1038/sj.emboj.7600239 Published online 13 May 2004 |
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| HCMV IE2-mediated inhibition of HAT activity downregulates p53 function |
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| Chih-Hung Hsu1, 2, Margaret D T Chang1, Kang-Yu Tai2, Yu-Ting Yang2, Pei-Shan Wang2, Chi-Ju Chen3, Yan-Hsiung Wang4, Sheng-Chung Lee4, Cheng-Wen Wu2, 5 and Li-Jung Juan2 |
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1 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 2 President Laboratory, National Health Research Institutes, Taipei, Taiwan 3 Institute of Microbiology, National Yang-Ming University, Taipei, Taiwan 4 Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan 5 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan To whom correspondence should be addressed Li-Jung Juan, President Laboratory, National Health Research Institutes, 128 Yen-Chiu-Yuan Road, Sec. 2, Taipei 115, Taiwan. Tel.: +886 2 26523075; Fax: +886 2 27829142; E-mail: ljjuan@nhri.org.tw Received 25 July 2003; Accepted 21 April 2004; Published online 13 May 2004. |
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| Abstract |
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| Targeting of cellular histone acetyltransferases (HATs) by viral proteins is important in the development of virus-associated diseases. The immediate-early 2 protein (IE2) of human cytomegalovirus (HCMV) binds to the tumor suppressor, p53, and inactivates its functions by unknown mechanisms. Here, we show that IE2 binds to the HAT domain of the p53 coactivators, p300 and CREB-binding protein (CBP), and blocks their acetyltransferase activity on both histones and p53. The minimal HAT inactivation region on IE2 involves the N-terminal 98 amino acids. The in vivo DNA binding of p53 and local histone acetylation on p53-dependent promoters are all reduced by IE2, but not by mutant IE2 proteins that lack the HAT inhibition region. Furthermore, the p53 acetylation site mutant, K320/373/382R, retains both DNA binding and promoter transactivation activity in vivo and these effects are repressed by IE2 as well. Together with the finding that only wild-type IE2 exerts an antiapoptotic effect, our results suggest that HCMV IE2 downregulates p53-dependent gene activation by inhibiting p300/CBP-mediated local histone acetylation and that IE2 may have oncogenic activity. |
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| Keywords: IE2, HAT, HCMV, p53 |
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