Cell Cycle Regulation by Spy1

One of the major foci of our group is to elucidate the function and regulation of the human cell cycle protein Speedy (Spy1; SPDYA). Spy1 is an unusual cell cycle protein in that it can activate Cyclin Dependent Kinases (CDKs) in the absence of the typical post-translational modifications on the CDK. Spy1 binds directly to the G1/S CDK, CDK2, and the G2/M CDK, CDK1, to activate them and promote cell proliferation and oocyte maturation. Of major interest to us, this atypical activation of the CDK allows Spy1 to promote cell growth and division in the presence of quiescent/senescent stimuli. Why would an organism evolve such a mechanism? Our group and others have shown that Spy1 is capable of overriding the DNA damage response and we hypothesize that the endogenous function of this protein is in re-entering the cell cycle during normal development and following repair of unfavorable cellular conditions. We and others have demonstrated that inappropriate regulation of this protein can lead to tumorigenesis in several systems. We further hypothesize that Spy1 represents a novel and potentially powerful drug target in specific forms of cancer. We have a number of models that we are studying this in: 1. We study brain and mammary gland normal development using mouse and in vitro cell systems. 2. We study implications in tumorigenesis using transgenic mouse models, xenograph transplants in mouse and zebrafish and human primary and immortalized cells.