Towards DNA-damage induced autophagy: A Boolean model of p53-induced cell fate mechanisms.
DNA Repair (Amst)
; 96: 102971, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-32987354
How a cell determines a given phenotype upon damaged DNA is an open problem. Cell fate decisions happen at cell cycle checkpoints and it is becoming clearer that the p53 pathway is a major regulator of cell fate decisions involving apoptosis or senescence upon DNA damage, especially at G1/S. However, recent results suggest that this pathway is also involved in autophagy induction upon DNA damage. To our knowledge, in this work we propose the first model of the DNA damage-induced G1/S checkpoint contemplating the decision between three phenotypes: apoptosis, senescence, and autophagy. The Boolean model is proposed based on experiments with U87 glioblastoma cells using the transfection of miR-16 that can induce a DNA damage response. The wild-type case of the model shows that DNA damage induces the checkpoint and the coexistence of the three phenotypes (tristable dynamics), each with a different probability. We also predict that the positive feedback involving ATM, miR-16, and Wip1 has an influence on the tristable state. The model predictions were compared to experiments of gain and loss of function in other three different cell lines (MCF-7, A549, and U2OS) presenting agreement. For p53-deficient cell lines such as HeLa, H1299, and PC-3, our model contemplates the experimental observation that the alternative AMPK pathway can compensate this deficiency. We conclude that at the G1/S checkpoint the p53 pathway (or, in its absence, the AMPK pathway) can regulate the induction of different phenotypes in a stochastic manner in the U87 cell line and others.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Dano ao DNA
/
Transdução de Sinais
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Proteína Supressora de Tumor p53
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Pontos de Checagem da Fase G1 do Ciclo Celular
/
Modelos Genéticos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
DNA Repair (Amst)
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Holanda