In higher eukaryotes, cell cycle progression is driven by a family of heterodimeric protein kinases, the cyclin-dependent kinases, formed through association of a catalytic CDK subunit with a regulatory cyclin subunit. Activation of these kinases, considered as the cell cycle engines, is a complex and finely regulated process, involving protein/protein interactions and reversible phosphorylation/dephosphorylation events.
Mechanisms regulating cell cycle progression are essential for maintaining cellular homeostasis and their deregulation, associated with unrestricted cell proliferation constitutes a major hallmark of cancer. A large number of studies document overexpression, hyperactivation or alternative splicing of several kinases and phosphatases that control cell cycle progression in a wide range of human cancers, including breast, ovarian, prostate, colorectal and lung cancer, lymphoma, myeloma and sarcoma.
In most cancer cells, CDK/Cyclins together with several of their regulatory kinases and phosphatases are expressed or activated in an aberrant fashion, which has direct consequences on cell proliferation. Given the central role of these enzymes in cell cycle regulation and their implication in checkpoint mechanisms, these enzymes constitute attractive targets for development of selective inhibitors for anti-tumoral chemotherapies.
Our objective consists in designing biosensors
to detect differences in expression or activation of these enzymes, and in developing inhibitors
intended to block these processes.