Journal
FEBS LETTERS
Volume 594, Issue 2, Pages 227-239Publisher
WILEY
DOI: 10.1002/1873-3468.13615
Keywords
ATMmiR-34a-5p axis; Boolean model; G1/S checkpoint; p21; Senescence-Apoptosis switch
Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [145708/2017-9]
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MicroRNA-34a-5p regulates the G1/S checkpoint in non-small cell lung cancer (NSCLC) cells. Forced expression of miR-34a-5p enhances p21 expression and promotes cellular senescence, whereas knockout of miR-34a-5p decreases senescence and increases apoptosis. This suggests that p21 is the main effector of a senescence-apoptosis switch in NSCLC cells; however, the molecular mechanisms controlling this switch are unclear. In this work, we propose a Boolean model of G1/S checkpoint regulation, contemplating the regulatory influences of p21 by miR-34a-5p. The predicted probabilities of our model are in excellent agreement with experimental data. Our model supports that p21 is the main effector of a senescence/apoptosis switch and that the disruption of the positive feedback involving ATM, miR-34a-5p, and the histone deacetylase HDAC1 abrogates senescence.
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