A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence.
PLoS Comput Biol
; 13(12): e1005741, 2017 Dec.
Article
em En
| MEDLINE
| ID: mdl-29206223
ABSTRACT
Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Transdução de Sinais
/
Senescência Celular
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
PLoS Comput Biol
Assunto da revista:
BIOLOGIA
/
INFORMATICA MEDICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha