Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins.
Proc Natl Acad Sci U S A
; 109(8): 2754-9, 2012 Feb 21.
Article
en En
| MEDLINE
| ID: mdl-21697511
ABSTRACT
Cyclin-dependent kinase subunit (Cks) proteins are small cyclin-dependent kinase-interacting proteins that are frequently overexpressed in breast cancer, as well as in a broad spectrum of other human malignancies. However, the mechanistic link between Cks protein overexpression and oncogenesis is still unknown. In this work, we show that overexpression of Cks1 or Cks2 in human mammary epithelial and breast cancer-derived cells, as well as in other cell types, leads to override of the intra-S-phase checkpoint that blocks DNA replication in response to replication stress. Specifically, binding of Cks1 or Cks2 to cyclin-dependent kinase 2 confers partial resistance to the effects of inhibitory tyrosine phosphorylation mediated by the intra-S-phase checkpoint, allowing cells to continue replicating DNA even under conditions of replicative stress. Because many activated oncoproteins trigger a DNA damage checkpoint response, which serves as a barrier to proliferation and clonal expansion, Cks protein overexpression likely constitutes one mechanism whereby premalignant cells can circumvent this DNA damage response barrier, conferring a proliferative advantage under stress conditions, and therefore contributing to tumor development.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
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Daño del ADN
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Proteínas Portadoras
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Proteínas Oncogénicas
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Quinasas Ciclina-Dependientes
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Proteínas de Ciclo Celular
Límite:
Animals
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Humans
Idioma:
En
Año:
2012
Tipo del documento:
Article