Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response
AuthorsCastillo, Jonathan Patrick
Frame, Fiona M.
Rogoff, Harry A.
Pickering, Mary T.
Yurochko, Andrew D.
Kowalik, Timothy F.
UMass Chan AffiliationsDepartment of Molecular Genetics and Microbiology
Graduate School of Biomedical Sciences
Document TypeJournal Article
Keywords1-Phosphatidylinositol 3-Kinase; Animals; Cell Cycle; Cell Cycle Proteins; Cell Line; Cyclin-Dependent Kinase Inhibitor p21; Cytomegalovirus; DNA-Binding Proteins; Fibroblasts; G1 Phase; Immediate-Early Proteins; Protein-Serine-Threonine Kinases; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Viral Proteins
Medicine and Health Sciences
MetadataShow full item record
AbstractHuman 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 p19(Arf) 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.
SourceJ Virol. 2005 Sep;79(17):11467-75. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33365
Related ResourcesLink to article in PubMed
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