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Cell cycle and DNA damage response regulation by Spy1 and the intersection of FGFR and NFkappaB pathways

Chris McAndrew

Appointment Period: 2009-2010, Grant Years: [25]

Chris McAndrewUnderstanding the activation and regulatory functions of cyclin dependent kinases and their inhibitors is of great importance to cancer biology. Experiments from our lab and others have identified the Speedy/RINGO family of proteins as important regulators of mammalian cell cycle control. I have shown that Spy1 activates CDKs and stimulates p27 degradation, thereby relieving an important cell cycle progression restraint. I have also demonstrated that Spy1 can directly activate CDK2 to phosphorylate p27 on Thr187, thereby targeting it for degradation and promoting S-phase entry. We have also shown that Spy1 is a component of the mammalian DNA damage response, preventing the DNA damage response and enhancing the survival of cells treated with DNA damaging agents. The novel modes of CDK regulation by Speedy/RINGO proteins may be important during cell cycle transitions, in the tolerance of normal intrinsic damage or in response to exogenous DNA damage, processes critical for cancer formation.

Misregulation of FGFR signaling can lead to uncontrolled downstream signaling associated with many developmental syndromes and cancers. NFkappaB also regulates apoptosis and proliferation of many human cancers, and activation of inflammatory responses. Interestingly, our research identifies a novel link between FGFR signaling and the NFkappaB pathway. We show FGFR2 and FGFR4 interact with IKKbeta, a critical component of NFkappaB signaling. We demonstrate tyrosine phosphorylation of IKKbeta resulting from FGFR4 or FGFR2 expression, and show suppressed NFkappaB signaling upon FGFR activation, which is dependent upon FGFR kinase activity.

Gastwirt RF, Slavin DA, McAndrew CW, Donoghue DJ. Spy1 expression prevents normal cellular responses to DNA damage: inhibition of apoptosis and checkpoint activation. J Biol Chem. (2006) 281:35425-35. PMID: 16951407.

Gastwirt RF, McAndrew CW, Donoghue DJ. Speedy/RINGO regulation of CDKs in cell cycle, checkpoint activation and apoptosis. Cell Cycle. (2007) 6:1188-93. PMID: 17507798.

McAndrew CW, Gastwirt RF, Meyer AN, Porter LA, Donoghue DJ. Spy1 enhances phosphorylation and degradation of the cell cycle inhibitor p27. Cell Cycle. (2007) 6:1937-45. PMID: 17671428.

Meyer AN, McAndrew CW, Donoghue DJ. Nordihydroguaiaretic acid inhibits an activated fibroblast growth factor receptor 3 mutant and blocks downstream signaling in multiple myeloma cells. Cancer Res. (2008) 68:7362-70. PMID: 18794123; PMC2745924.

McAndrew, CW, RF Gastwirt and DJ Donoghue (2008) Cell Cycle: Regulation. In "Wiley Encyclopedia of Chemical Biology" (N. R. Civjan, Ed.) John Wiley & Sons, Inc.

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

McAndrew CW, Gastwirt RF, Donoghue DJ. The atypical CDK activator Spy1 regulates the intrinsic DNA damage response and is dependent upon p53 to inhibit apoptosis. Cell Cycle. (2009) 8:66-75. PMID: 19106603; PMC2782695.

Drafahl, KA., McAndrew CW, Meyer AN, Haas M, Donoghue DJ. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB Signaling. PLoS One. (2010) 5(12):e14412. PMID: 21203561; PMCID: PMC3008709.