Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Molecular Genetics and Microbiology
Medical Subject Headings
1-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
Life Sciences | Medicine and Health Sciences
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 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.
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Citation: J Virol. 2005 Sep;79(17):11467-75. Link to article on publisher's site
Journal of virology
Castillo, Jonathan Patrick; Frame, Fiona M.; Rogoff, Harry A.; Pickering, Mary T.; Yurochko, Andrew D.; and Kowalik, Timothy F., "Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response" (2005). GSBS Student Publications. 189.