Understanding what factors regulate CDK2 and p27 is extremely important in the study of normal cell cycle progression and recently in the temporal control of meiosis. Misregulation of CDKs, cyclins and p27 are associated with oncogenesis. Our lab demonstrated that a protein in the Speedy/RINGO family, called Spy1, interacts with p27 and CDK2. Additionally, Spy1 overexpression has been found in cancer tissues and cancer cell lines. The loss of control over a molecule like Spy1, which has such potent effects on CDK activation, growth control, checkpoints and apoptosis, poses a threat to genomic stability, and may be oncogenic in nature. Recently, I have shown Spy1 overexpression promotes CDK2 activation and leads to enhanced p27 phosphorylation and degradation. Currently, I am working on elucidating other substrates of Spy1/CDK complexes using bulky ATP analogues and mutant kinases in a method developed by Shokat at UCSF. It may prove invaluable to know the implications of Speedy/RINGO family members in the diagnosis and treatment of cancer. The outcome of common and experimental chemotherapeutic and anti-cancer drugs may be greatly influenced by the status of the Speedy/RINGO family members. Future research should define an important role for this novel family of cell cycle regulators in cell biology and cancer biology.

PUBLICATIONS (resulting from this training)

McAndrew CW, Gastwirt RF, Donoghue DJ (2009). The atypical CDK activator spy1 regulates the intrinsic DNA damage response and is dependent upon p53 to inhibit apoptosis. Cell Cycle. 2009 Jan 1;8(1):66-75. PMID: 19106603

Drafahl, K. A., C. W. McAndrew, D. J. Donoghue (2009) Signaling from fibroblast growth factor receptors in development and disease. In "Handbook of Cell Signaling", Second Edition (R. Bradshaw & E. Dennis, Eds.) Oxford:Academic Press, pp. 1939-1948.

Kristine A. Drafahl, April N. Meyer, Christopher W. McCandrew, Daniel J. Donoghue. The novel interaction of FGFR4 and IKKbeta negatively regulates NF-kappaB activity. Manuscript in revision.