Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (8), p.2754-2759
• Main Authors: Liberal, Vasco, Martinsson-Ahlzén, Hanna-Stina, Liberal, Jennifer, Spruck, Charles H, Widschwendter, Martin, McGowan, Clare H, Reed, Steven I
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Breast cancer; BREAST CANCER SPECIAL FEATURE; breast neoplasms; carcinogenesis; Carrier Proteins - metabolism; CDC2-CDC28 Kinases; Cell cycle; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell lines; Cell proliferation; Cells; Cyclin-dependent kinase; Cyclin-dependent kinase 2; Cyclin-Dependent Kinases - metabolism; Cyclins; DNA; DNA biosynthesis; DNA Damage; DNA replication; HEK293 Cells; Humans; Hydroxyurea - pharmacology; Kinases; Malignancy; Mice; Oncogene Proteins - metabolism; Phosphorylation; Protein Kinases - metabolism; Proteins; Replication; S Phase - drug effects; Signal Transduction - drug effects; Somatic cells; Stress; Thymidine - pharmacology; Tumorigenesis; Tumors; Tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1102434108

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.