The Kindlin2-p53-SerpinB2 signaling axis is required for cellular senescence in breast cancer.
Cell Death Dis
; 10(8): 539, 2019 07 15.
Article
em En
| MEDLINE
| ID: mdl-31308359
ABSTRACT
In cancer, cellular senescence is a complex process that leads to inhibition of proliferation of cells that may develop a neoplastic phenotype. A plethora of signaling pathways, when dysregulated, have been shown to elicit a senescence response. Two well-known tumor suppressor pathways, controlled by the p53 and retinoblastoma proteins, have been implicated in maintaining the cellular senescence phenotype. Kindlin-2, a member of an actin cytoskeleton organizing and integrin activator proteins, has been shown to play a key role in the regulation of several hallmarks of several cancers, including breast cancer (BC). The molecular mechanisms whereby Kindlin-2 regulates cellular senescence in BC tumors remains largely unknown. Here we show that Kindlin-2 regulates cellular senescence in part through its interaction with p53, whereby it regulates the expression of the p53-responsive genes; i.e., SerpinB2 and p21, during the induction of senescence. Our data show that knockout of Kindlin-2 via CRISPR/Cas9 in several BC cell lines significantly increases expression levels of both SerpinB2 and p21 resulting in the activation of hallmarks of cellular senescence. Mechanistically, interaction between Kindlin-2 and p53 at the promotor level is critical for the regulated expression of SerpinB2 and p21. These findings identify a previously unknown Kindlin-2/p53/SerpinB2 signaling axis that regulates cellular senescence and intervention in this axis may serve as a new therapeutic window for BCs treatment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Proteína Supressora de Tumor p53
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Senescência Celular
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Inibidor 2 de Ativador de Plasminogênio
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Proteínas do Citoesqueleto
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Proteínas de Membrana
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Proteínas Musculares
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article