title: Disruption of the p53-p21 pathway inhibits efficiency of the lytic-replication cycle of herpes simplex virus type 2 (HSV-2).
abstract: Cellular p53 and its downstream mediator p21, the major cellular growth suppression and DNA repair markers, have recently been implicated in viral amplification. Here, we show that herpes simplex virus type 2 (HSV-2) infection of both HCT116 p53(+/+)and NIH3T3 cells resulted in sustained increases of p21. HSV-2 infection did not increase cellular p53 expression, but led to phosphorylation of this protein at Ser20. This phosphorylation was accompanied by the increase of p21 protein levels. Furthermore, specific knockdown of endogenous p21 by siRNAs severely impaired virus production represented by HSV envelope glycoprotein B (gB) expression and progeny virus titers. Disruption of the p53-p21 pathway by either knocking down p53 in HCT116 p53(+/+) and NIH3T3 cells or using p53-deficient HCT116 p53(-/-) cells, led to a significant reduction of HSV-2 production. Together, these results suggest that the p53-p21 pathway is required for efficient HSV-2 lytic replication cycle. Because HSV infection induces the G0/G1 phase arrest at the early step of lytic-replication cycle, we propose that HSV-2 might hijack the cellular p53-p21 pathway to arrest the host cell cycle at G0/G1 phase, blocking cellular DNA synthesis, for its own benefit, i.e., to favor its own viral replication by avoiding competition in generating viral nucleotide pools.
authors: Department of Microbiology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, PR China.
authors: Qi
authors: Q
authors: Zhou
authors: Meng
authors: M
authors: Zhu
authors: Hao
authors: H
authors: Zhang
authors: Ting
authors: T
authors: Yi
authors: John D
authors: JD
authors: Klena
authors: Yihong
authors: Y
authors: Peng
mesh_terms: D000818:Animals; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53