The expression of p16INK4a tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication.
The human cytomegalovirus (HCMV) induces a replicative senescence program after arresting host cell cycle progression so as to create a favorable environment for its replication. Here, we report that HCMV infection stimulates the expression of p16(INK4a), a direct effector of the senescence phenotype. The increase in p16(INK4a) gene expression was due to an increase in gene transcription, since the expression of a reporter gene driven by the p16(INK4a)-encoding CDKN2A gene promoter was strongly induced by HCMV infection. The results of deletion and mutational analysis of the CDKN2A promoter further suggest the involvement of Ets transcription factors in HCMV-mediated stimulation of p16(INK4a) gene expression. The significance of p16(INK4a) upregulation during the HCMV replicative cycle is underscored by the finding that virus replication was severely impaired in fibroblasts homozygous for an intragenic deletion in CDKN2A locus and devoid of functional p16(INK4a). Moreover, a retrovirus-mediated p16(INK4a) small interfering RNA (p16-siRNA) effectively reduced viral replication, thus providing direct evidence that p16(INK4a) upregulation plays a positive role for HCMV replication.
Zannetti
Claudia
C
Department of Public Health and Microbiology, University of Torino, Via Santena, 9-10126 Torino, Italy.
Mondini
Michele
M
De Andrea
Marco
M
Caposio
Patrizia
P
Hara
Eiji
E
Peters
Gordon
G
Gribaudo
Giorgio
G
Gariglio
Marisa
M
Landolfo
Santo
S
D019677:Artificial Gene Fusion; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003587:Cytomegalovirus / Q000502:physiology*; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis; D005347:Fibroblasts / Q000821:virology; D017353:Gene Deletion; D020868:Gene Silencing; D017930:Genes, Reporter / Q000235:genetics / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000502:physiology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D050783:Proto-Oncogene Proteins c-ets; D034741:RNA, Small Interfering; D008156:Luciferases