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

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.

Effects of Human Cytomegalovirus Immediate-Early Proteins on p53-mediated Apoptosis in Coronary Artery Smooth Muscle Cells

“…The capacity of IE2-84 to inhibit a p53-dependent signaling pathway that leads to p21 induction and apoptosis is consistent with previous studies indicating that IE2-84 binds to p53 and inhibits its capacity to transactivate a promoter controlling a downstream reporter gene. 1,4 In contrast, the other viral IE proteins appear, like IE1-72, to have proapoptotic effects.…”

“…3 This proliferative signal may relate to the ability of the immediate-early (IE) gene product of HCMV, IE2-84, to bind p53 and inhibit its transactivational activity. 1,4 Because p53 transcriptionally regulates gene products such as the cyclin-dependent kinase inhibitor p21, which in turn regulates cell cycle progression, 5 the inhibitory effect of IE2-84 on p53 could increase smooth muscle cell (SMC) proliferation and thereby increase SMC accumulation. However, the extent of SMC accumulation is not simply a function of proliferation rate.…”

Cellular Transformation by the HTLV-I Tax Protein, a Jack-of-All-Trades

“…In virally transformed cells, p53 is a major target for inactivation, as many viral oncogenes (e.g. SV40 large T-Ag, hepatitis B X protein, adenovirus E4 orf6, cytomegalovirus IE2, and the human papillomavirus E6 and E7 proteins) interfere with p53 function (Prives and Manfredi, 1993;Demers et al, 1994Demers et al, , 1996Truant et al, 1995;Dobner et al, 1996;Tsai et al, 1996). Loss of p53 function prevents proper G 1 /S arrest, p53-mediated apoptosis, and DNA repair, all of which contribute to cellular transformation.…”

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

“…Human cytomegalovirus (HCMV) (Speir et al, 1994;Muralidhar et al, 1996;Tsai et al, 1996;Bonin & McDougall, 1997;Castillo et al, 2005) and possibly HHV-6A (Kashanchi et al, 1997;Takemoto et al, 2005) and HHV-6B (De Bolle et al, 2004;Takemoto et al, 2004;Øster et al, 2005) interfere with the tumour suppressor protein p53. The major functions of p53 are associated with maintaining the integrity of the genome by inducing cell-cycle arrest, senescence or apoptosis (Jin & Levine, 2001).…”