HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway.
Oncogene
; 23(28): 4807-17, 2004 Jun 17.
Article
em En
| MEDLINE
| ID: mdl-15077164
ABSTRACT
Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (deltapsim). Loss of deltapsim was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic alpha- and beta-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Papillomaviridae
/
Fatores de Transcrição
/
Proteínas Nucleares
/
Apoptose
/
Proteínas de Ciclo Celular
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Proteínas de Ligação a DNA
/
Inibidores Enzimáticos
/
Inibidores de Histona Desacetilases
Limite:
Humans
Idioma:
En
Revista:
Oncogene
Ano de publicação:
2004
Tipo de documento:
Article