Transcriptional networks and cellular senescence in human mammary fibroblasts.
Mol Biol Cell
; 16(2): 943-53, 2005 Feb.
Article
em En
| MEDLINE
| ID: mdl-15574883
ABSTRACT
Senescence, the molecular program that limits the finite proliferative potential of a cell, acts as an important barrier to protect the body from cancer. Techniques for measuring transcriptome changes and for modulating their expression suggest that it may be possible to dissect the transcriptional networks underlying complex cellular processes. HMF3A cells are conditionally immortalized human mammary fibroblasts that can be induced to undergo coordinated senescence. Here, we used these cells in conjunction with microarrays, RNA interference, and in silico promoter analysis to promote the dissection of the transcriptional networks responsible for regulating cellular senescence. We first identified changes in the transcriptome when HMF3A cells undergo senescence and then compared them with those observed upon replicative senescence in primary human mammary fibroblasts. In addition to DUSP1 and known p53 and E2F targets, a number of genes such as PHLDA1, NR4A3, and a novel splice variant of STAC were implicated in senescence. Their role in senescence was then analyzed by RNA silencing followed by microarray analysis. In silico promoter analysis of all differential genes predicted that nuclear factor-kappaB and C/EBP transcription factors are activated upon senescence, and we confirmed this by electrophoretic mobility shift assay. The results suggest a putative signaling network for cellular senescence.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
/
Senescência Celular
/
Fibroblastos
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Mol Biol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Reino Unido