My laboratory has combined biochemical, molecular, cellular, and genetic approaches to investigate the roles of CDK inhibitors in differentiation, development, and cancer biology. An additional major focus of the laboratory is directed towards understanding how these gene products are regulated to accomplish these roles.Over the last 40+ years a colossal worldwide effort was made to understand how cells proliferate and divide, as this clearly contributed to the development of cancer and the biological integrity of organisms. Today, because of work conducted in model systems (yeast, worms, flies), cancer and normal mammalian cell lines, and rodents and higher mammals we have a detailed understanding of the conserved mechanisms by which cells choose to enter and exit the cell cycle, and an emerging understanding of the molecular machines controlling DNA replication and cell division and their regulation. Today, attention is turning to understand how non-proliferating cells, cells that have exited the cell cycle, retain their capacity to re-enter when necessary.
In the past, this labs study of G1 cyclins and the Kip family of cdk inhibitors contributed greatly to our understanding of the consequences, both cellular and organismal, of dysregulating the decision of mammalian cells to enter and exit the cell cycle during development and during the formation and progression of cancer cells. Thus, it is well positioned to now turn its attention to understanding how quiescent non-cycling cells maintain themselves in a state in which it might be years before they re-enter the mitotic cell cycle.
Work in our group over the last four years studying the effect of CDK4/6 inhibition in cancer cells has uncovered a new relationship between quiescence and senescence, a more permanent form of cell cycle exit from which cells cannot re-enter the cell cycle irreversible. We suspect that similar to the molecular machine that governs the decision to enter/exit the cell cycle, a small set of genetic elements conspire to control the reversible/irreversible decision operating to control the progression of quiescent cells into senescence, a transition that we call senescence after growth arrest or SAGA.