The Cell Cycle Regulators
The cell cycle relies on the efforts of multiple regulators to keep it going successfully. The scientific community has just recently acknowledged the presence of cell cycle regulators. Experiments conducted during the 1960’s through the 1980’s eventually led to an established idea of cell cycle regulation. Lee Hartwell, Paul Nurse, and Tim Hunt received a Nobel Prize in Physiology or Medicine in 2001 for their efforts in this category.
Cell cycle regulation is necessary for cell survival. Regulators, generally speaking, have two major capabilities: firstly, detecting and repairing damaged DNA and secondly, preventing uncontrolled cell division. There are two key classes of regulatory molecules. The first includes cyclins, a regulator subunit. The second is that of cyclin-dependent kinases (CDKs), a catalytic subunit. Cyclins are synthesized in the cell cycle and have no catalytic activity. CDKs on the other hand, are simply found within the cell (not created during the cell cycle) and only become active once bound with cyclins. Although there are many types of CDKs, for simplicity’s sake, we will focus on a few. CDK-1 is commonly found/used in the G2 and M phases of the cell cycle; CDK-4 is found/used during the G1 phase.
The combinations of cyclins and cyclin-dependent kinases (CDKs) work together to phosphorylate and activate (or inactivate) target proteins in the following steps of the cell cycle. Different combinations determine which target protein will be affected. In general, the activated complexes have the ability to prepare the cell for the S phase of the cell cycle and to promote expression of S cyclins and enzymes that DNA replication requires. They also have the ability to degrade S phase inhibitors via ubiquitination.
Each activated combination has a specific role it plays in regulation. S cyclin-CDK complexes phosphorylate proteins in pre-replication complexes, therefore activating them, and also prevent new, unwanted complexes from forming. These S cyclin-CDK combinations have the specific job of ensuring only one copy of each genome. Without them, a disaster would happen. Mitotic cyclin-CDK complexes play an entirely different role. They initiate mitosis by stimulating the proteins involved in the processes of mitotic spindle creation and chromosome condensation. Cyclin D and CDK-4 complexes phosphorylate the protein called retinoblastoma (Rb). When this happens, the Rb protein breaks away from the Rb/E2F pathway and activates E2F. If, on the other hand, Rb remains bonded to the pathway, it will inhibit its use. Cyclin E and CDK-2 complexes have the ability to move the cell from the G1 to the S phase of the cell cycle. Cyclin B and CDK-2 combinations move it from the G2 to the M phase, and also cause the breakdown of the nuclear envelope so that mitosis can begin.
Cell cycle regulation also includes a subcategory of inhibitors. Inhibitory proteins include CDK inhibitory proteins (the CIP family) and kinase inhibitory proteins (the KIP family). They alt the G1 phase of the cell cycle by inactivating cyclin-CDK complexes. More inhibitors include the INK4a/ARF family (which bond to CDK-4, preventing degradation and halting the G1 phase), positive and negative phosphorylation of individual CDKs, protein degradation, and regulated destruction (which ensure the cell cycle won’t “roll backwards”).
In order for the cell cycle to occur, and for DNA checkpoints and cyclin-CDK complexes to be effective, many intracellular organelles must be involved.