Human Cytomegalovirus Immediate-Early Protein IE2 Tethers a Transcriptional Repression Domain to p53

Shan-Chun Chen,Guang-Hsiung Kou,Hsiu-Lan Tsai,Cheng-Wen Wu,Young-Sun Lin

doi:10.1074/jbc.271.7.3534

Abstract

The IE2 gene of human cytomegalovirus has been implicated in the development of coronary restenosis, and the gene product appears to inhibit p53-dependent transactivation. Here we describe an analysis of the IE2-p53 interaction. Repression of p53 function by IE2 requires two separable domains of IE2. The N terminus of IE2 interacts with p53. IE2 has little effect on the ability of p53 to bind specific DNA sequences. Reduction of the transactivation activity of p53 is caused by a transcriptional repression function contributed by the C-terminal domain of IE2. These findings suggest that IE2 may function as a transcriptional repressor, which is recruited to p53's target genes by interacting with p53.

Highlights

The tumor suppressor p53 protein is an important negative regulator of cell proliferation [1,2,3,4,5]
Loss of p53 function results in genome instability [6, 7] and eliminates growth arrest at the G1 phase in response to inadequate or detrimental growth conditions (8 –10). p53 functions as a typical eukaryotic transcription factor; it binds to specific DNA sequences termed p53-responsive elements1 [8, 11,12,13,14,15,16] and stimulates transcription of the target genes [11, 17,18,19]
P53 is organized into three functional domains: an N-terminal domain, involved in transcriptional activation; a central domain, mediating specific DNA binding; and a C-terminal domain, responsible for oligomerization, transcriptional repression, and nonspecific DNA binding [3, 24, 25]

Summary

Introduction

The tumor suppressor p53 protein is an important negative regulator of cell proliferation [1,2,3,4,5]. P53 represses transcription of many viral and cellular genes, which apparently do not have PRE (20 –22) This function, probably reflecting general negative effects on cellular growth via the induction of WAF1/CIP1 by p53 [23], requires the transactivation activity of p53. All of the major classes of small DNA tumor viruses that replicate in mammalian nuclei encode immediate-early gene products to overcome the negative effects of p53 on cell proliferation. The inactivation of p53 function by the viral immediate-early proteins results in promoting cell. The replication strategy of herpesviruses must be fundamentally different from that of small DNA viruses, it seems logical that they still have to deal with the negative effect imposed by p53 on cell proliferation so that host cells can enter the S-phase of the cell cycle and promote viral replication. Recent evidence has demonstrated that the C terminus of IE2 is involved in such protein activities as activation, autoregulation, and binding to retinoblastoma protein, TBP, and TFIIB (Ref. 33 and references therein)

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Results

Conclusion