Three tyrosine kinases are able to phosphorylate and inhibit cyclin-dependent kinase inhibitor 1B (CDKN1B; also known as p27), giving rise to chemotherapy resistance and poor cancer prognosis.
CDKN1B (cyclin-dependent kinase inhibitor 1B; also known as p27) protein expression is reduced in 60% of human cancers, and is indicative of poor prognosis and chemotherapy resistance. Slingerland, Hengst and colleagues, and Hengst, Kriwacki and colleagues have identified a new CDKN1B regulatory pathway, mediated by oncogenic tyrosine kinases.
Image courtesy of Richard Kriwacki, Ludger Hengst, with thanks to Darcie Miller, K. Gopal Murti and Ken Barnes.
CDKN1B, a key cyclin-dependent kinase (CDK) inhibitor, is targeted for degradation as cells enter S-phase by the CDK–cyclin-mediated phosphorylation of T187. How CDK–cyclin becomes sufficiently activated to phosphorylate CDKN1B has been unclear. Hengst, Kriwacki and colleagues showed that CDKN1B is phosphorylated in vitro on Y88 by the LYN and BCR–ABL tyrosine kinases, and that this phosphorylation is increased in BCR–ABL-transformed cells. Slingerland, Hengst and colleagues showed that CDKN1B is phosphorylated by the SRC tyrosine kinase (which is frequently activated in oestrogen-receptor-positive breast tumours) on Y74 and Y88 in vitro and in breast cancer cell lines. Furthermore, both groups showed that tyrosine phosphorylation reduced the ability of CDKN1B to inhibit G1 CDK–cyclin activity, but CDKN1B–CDK–cyclin complex formation was only partially reduced. Hengst, Kriwacki and colleagues showed that Y88 phosphorylation ejects an inhibitory helix of CDKN1B from the active site of CDK2, resulting in partial CDK2–cyclin A kinase activation (shown in yellow in the figure). Moreover, Y88 phosphorylation by ABL or LYN kinases increased T187–CDKN1B phosphorylation in transformed cells. Slingerland, Hengst and colleagues showed that the ectopic expression of SRC and oestrogen stimulation increased CDKN1B tyrosine phosphorylation, which was followed by T187–CDKN1B phosphorylation and reduced protein levels in breast cancer cells. Therefore, both groups propose that CDKN1B tyrosine phosphorylation functions as a primer for T187–CDKN1B phosphorylation by alleviating CDKN1B inhibition of CDK2–cyclin activity.
The groups then investigated the relevance of this novel CDKN1B regulation to cancer. Slingerland, Hengst and colleagues showed by immunohistochemistry that 40% of 482 breast tumour samples showed a correlation between activated SRC and reduced levels of CDKN1B. Additionally, cells resistant to the anti-oestrogen drug tamoxifen were sensitized when treated with AZD0350, an inhibitor of SRC currently in phase II clinical trials. Furthermore, Hengst, Kriwacki and colleagues showed that imatinib (which inhibits BCR–ABL) reduced Y88–CDKN1B phosphorylation in K562 leukaemia cells, resulting in increased stability of CDKN1B.
Therefore, both groups have identified a CDKN1B-regulatory pathway that links oncogenic tyrosine kinases to the downregulation of CDKN1B protein levels. It is possible that resistance to chemotherapeutics, such as imatinib and tamoxifen, might be promoted by the oncogenic activation of tyrosine kinases that target CDKN1B for degradation, which consequently drives cell proliferation by amplifying CDK–cyclin activity.
Gemma Alderton
References
Chu, I. et al. p27 phosphorylation by Src regulates inhibition of cyclin E-cdk2. Cell128, 281–294 (2007) | Article | PubMed |
Grimmler, M. et al. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by onncogenic tyrosine kinases. Cell128, 269–280 (2007) | Article | PubMed |
60% of human cancers, and is indicative of poor prognosis and chemotherapy resistance. Slingerland, Hengst and colleagues, and Hengst, Kriwacki and colleagues have identified a new CDKN1B regulatory pathway, mediated by oncogenic tyrosine kinases.
