Transcriptional factor HBP1 targets P16(INK4A), upregulating its expression and consequently is involved in Ras-induced premature senescence.
Oncogene
; 29(36): 5083-94, 2010 Sep 09.
Article
em En
| MEDLINE
| ID: mdl-20581871
ABSTRACT
Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras- and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16(INK4A) cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16(INK4A) gene contains an HBP1-binding site at position -426 to -433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16(INK4A) gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16(INK4A) gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16(INK4A) to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Proteínas de Grupo de Alta Mobilidade
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Proteína Oncogênica p21(ras)
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Senescência Celular
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Inibidor p16 de Quinase Dependente de Ciclina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Oncogene
Ano de publicação:
2010
Tipo de documento:
Article