Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response
Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response
复制标题
DOI：
10.1128/jvi.79.17.11467-11475.2005
复制
发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Kowalik, TF
中科院分区：
文献类型：
--
作者：
Castillo, JP;Frame, FM;Kowalik, TF
人类巨细胞病毒 (HCMV) 编码多种可调节细胞周期机制组成部分的蛋白质。 UL123 基因产物 IE1-72 与 Rb 相关的 p107 蛋白结合，并解除其对 E2F 响应启动子的抑制；然而，它无法诱导野生型（p53（+/+））细胞中的静止细胞进入S期。 IEl-72还通过未知机制诱导p53积累。我们在此提供的证据表明IEl-72可能通过增加p19(Arf)的水平并通过诱导p53在Ser15处的磷酸化来激活p53途径。发现仅由IE1-72表达或HCMV感染引起的该残基的磷酸化依赖于共济失调-毛细血管扩张突变激酶。 IE2-86 表达导致 p53 磷酸化，并可能导致 HCMV 感染细胞中的这种表型。我们还发现IEl-72通过消除p53核穿梭来促进p53核积累。这些事件导致p53活性的刺激，导致瞬时表达IE1-72的细胞中细胞周期从G(1)期进展到S期的p53-和p21依赖性抑制。因此，像许多小DNA肿瘤病毒一样，HCMV感染后表达的第一个蛋白质激活宿主细胞的p53反应。
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. IEl-72 also induces p53 accumulation through an unknown mechanism. We present here evidence suggesting that IEl-72 may activate the p53 pathway by increasing the levels of p19(Arf) and by inducing the phosphorylation of p53 at Ser15. Phosphorylation of this residue by IEl-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 IEl-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 IEl-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.