Interplay between SCF and CDK complexes in the control of cellular proliferation

Altering the activity of cyclin-dependent kinases and SCF-based E3 ubiquitin ligases has detrimental consequences to normal cell division and cellular homeostasis. Therefore elucidating the substrates by which CDK and SCF complexes control cell division is essential for understanding how perturbing their activity leads to cellular transformation. This thesis identifies the elusive E3 ubiquitin ligase for cyclin D1, the SCFFBx4-alphaB crystallin complex, which targets Thr286-phosphorylated cyclin D1 for cytoplasmic destruction. In addition, this work describes how disruption of normal cyclin D1 localization and FBX4-mediated proteolysis significantly accelerates the development of mammary adenocarcinomas in mice. Finally, I also demonstrate that phosphorylation of MCM3 by CDK1 at an evolutionarily conserved site, Ser112, promotes loading of MCM3 onto chromatin and assembly of the MCM2-7 replicative DNA helicase. This thesis highlights the functional significance of the post-translational modification of a SCF substrate and of a CDK substrate, cyclin D1 and MCM3 respectively, as paradigms for the establishment of "on" and "off" programs required for the commitment to cell division and cell cycle transitions.