Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response

Abstract

Human cytomegalovirus (HCMV) encodes several proteins that can modulate components of the cell cycle machinery. The UL123 gene product, IE1-72, binds the Rb-related, p107 protein and relieves its repression of E2F-responsive promoters; however, it is unable to induce quiescent cells to enter S phase in wild-type (p53 ؉/؉ ) cells. IE1-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19Arf and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IE1-72 expression alone or HCMV infection is found to be dependent on the ataxia-telangiectasia mutated kinase. IE2-86 expression leads to p53 phosphorylation and may contribute to this phenotype in HCMV-infected cells. We also found that IE1-72 promotes p53 nuclear accumulation by abrogating p53 nuclear shuttling. These events result in the stimulation of p53 activity, leading to a p53-and p21-dependent inhibition of cell cycle progression from G 1 to S phase in cells transiently expressing IE1-72. Thus, like many of the small DNA tumor viruses, the first protein expressed upon HCMV infection activates a p53 response by the host cell.

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

“…Furthermore, many reports have described a viral connection between TP53 and cell cycle arrest. Herpesviruses, such as herpes simplex virus (40), human herpesvirus 6 (41), and human cytomegalovirus (42)(43)(44), cause cell cycle arrest via the TP53 pathway; however, the viral proteins responsible for TP53 stabilization and the precise mechanisms and significance of cell cycle arrest remain unknown. The data in this study might provide a clue to the mechanism and the significance of cell cycle arrest induced by these viruses.…”

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

“…Several herpesviruses, such as HSV (Boutell & Everett, 2004), EBV (Mauser et al, 2002), HCMV (Castillo et al, 2005) and HHV-6B (Øster et al, 2005), have been shown to induce phosphorylations at multiple sites in p53. Only two viruses, EBV and human T-cell lymphotropic virus type 1, have previously been reported to induce phosphorylation of human p53 at Ser392 (Pise-Masison et al, 1998;Mauser et al, 2002).…”

“…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).…”

“…Like HCMV (Castillo et al, 2005), HHV-6B is capable of inducing phosphorylation in the N terminus of p53 at Ser15 (Øster et al, 2005). Other human herpesviruses may also interfere with p53 functions.…”

Interference with Cell-Cycle Progression by Parasitic Genetic Elements: Sleeping Beauty Joins the Club

“…43 Human cytomegalovirus stimulates p53 activity, leading to a p21-dependent inhibition of cell cycle progression. 48 The EBVencoded protein ZTA was found to cause a G 1 -arrest by inducing p53 and the cdk inhibitors p21 and p27 as well as accumulation of hypophosphorylated (growth-suppressive) Rb. 45,49 Replication of MHV prevents cdk4/6 activity and subsequent Rb hyperphosphorylation by a reduction of G 1 cyclins (cyclin D1, D2, D3 and cyclin E).…”