Role of cyclin-dependent Kinase 5 in cell proliferation

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My research program is geared towards understanding how protein kinases regulate cell function. The focus is to unravel the molecular mechanisms by which cyclin dependent kinase 5 (cdk5) regulates specific cellular processes. Indeed, the phosphorylation mechanisms involving cdk5 are intriguing as mice lacking cdk5 exhibit embryonic lethality, indicating that cdk5 is essential for development and survival. My general hypothesis is that cdk5 is key to an elaborate system of protein-protein interactions and phosphorylation events in the mammalian cell. To address this premise, my broad research program encompasses questions that include: how cdk5 activity is regulated, what the molecular targets of cdk5 are and how cdk5 interacts with its targets, and how cdk5 participates in signaling pathways to regulate cell fate, including proliferation, differentiation, and apoptosis. Currently, our investigations are primarily directed at examining cdk5 regulation and role in spermiogenesis, cilia formation and function, and cell proliferation. Indeed, while cdk5 activity has mostly been associated with postmitotic neurons, there is now substantial evidence of apoptosis-independent cdk5 activity in proliferating cells. Interestingly, there are also new reports implicating a role for cdk5 in the cell cycle. Consistent with these findings, we recently observed that cdk5-/- embryos are bigger and have increased genomic DNA (gDNA) levels compared to their wt littermates. In addition, we found that cdk5-/- mouse embryonic fibroblasts (MEFs) proliferate at a faster rate than wt MEFs, supporting the idea of a novel function of cdk5 in cell proliferation. Therefore, my focus in this application is to explore my specific hypothesis that cdk5 serves to inhibit cell cycle progression. My specific objective is to utilize the cdk5 knockout system to: (i) investigate whether the increase in size of cdk5-/- mouse embryos is due to increased number of cells, (ii) determine the specific phase(s) of the cell cycle that is inhibited by cdk5, and (iii) investigate the molecular mechanism(s) by which cdk5 may inhibit the cell cycle. Understanding how cdk5 controls the cell cycle will further advance our knowledge of this fundamental cellular process.