Regulation and activity of cell cycle control factors in terminal cellular differentiation

grantor: University of TorontoCellular differentiation is a process in which multipotent stem cells undergo a series of genetic events that limit the number of eventual cell fates. Terminal differentiation is one final stage, where a number of functional and phenotypic changes occur giving rise to a characteristic appearance and function. No further cell fate choices are available to terminally differentiated cells. In many cases the terminally differentiated cell is no longer capable of proceeding through the cell cycle, and arrests permanently in a quiescent G0 state. Investigations using a number of model systems have determined that there is remarkable conservation between species, at both the sequence and the structural level, of the regulatory factors which control passage through the mitotic cell cycle (for reviews see: (1-4)). Factors that regulate progression through the cell cycle are likely to be intricately involved in the process of terminal differentiation. In this thesis, I have investigated the regulation of cell cycle factors, and the functional role of these factors and their interactions, during cellular differentiation. We found that members of the E2F, pRB, cyclin, cdk, and CKI family proteins are regulated in both neuronal and myogenic differentiation through a series of overlapping regulatory mechanisms. These mechanisms include alterations in transcription, phosphorylation, protein stability, and sub-cellular localization, as well as changes in subunit composition of kinase and transcription complexes. The net effect of these overlapping regulatory mechanisms is to suppress levels of free, active E2F transcription complexes, allowing cell cycle exit and terminal differentiation to occur.Ph.D