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.

The expression of p16INK4a tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication

DE ANDREA, Marco;CAPOSIO, Patrizia;GRIBAUDO, Giorgio;LANDOLFO, Santo Giuseppe
2006

Abstract

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.
349(1)
79
86
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXR-4JCCFY9-1&_user=525216&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000026382&_version=1&_urlVersion=0&_userid=525216&md5=c46edc2ee0fabeb24f37f7be25d33f7f
Human cytomegalovirus; replication; p16INK4a; senescence
ZANNETTI C; MONDINI M; DE ANDREA M; CAPOSIO P; HARA E; PETERS G; GRIBAUDO G; GARIGLIO M; LANDOLFO S
File in questo prodotto:
File Dimensione Formato  
Zannetti et al., Virology 2006.pdf

Accesso riservato

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 355.01 kB
Formato Adobe PDF
355.01 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/40322
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 9
social impact