The cell cycle is under strict control in most cells, the mechanics of which are somewhat understood. There are a number of proteins involved in the regulation of the cell cycle, the speed at which it traverses the various stages, and the various checkpoints which help to control these.
As a basic summary, there are various levels of machinery which allow the cell cycle to take place.
At the most basic level, there are the cyclin dependent kinases that, when activated, turn on progression through the cell cycle
Above this are the cyclins, molecules which are released in response to the various stimuli to activate the CDKs
Another level of proteins control activation of the cyclins. This is when it starts getting very complicated! There are proteins which stimulate progression through the cell cycle (such as MYC), and proteins which halt progression (such as RB1 and TP53).
There are hundreds of factors which can influence the pro- and anti-cell cycle progression pathways, either by themselves or by setting in motion a cascade of enzyme activations.
Cyclin Dependent Kinases (CDK)
These are proteins which become active when a cyclin protein binds to them. There are multiple types but only several are involved in the cell cycle. CDK4 and CDK6 are involved in G1 phase, CDK2 in G1 and S phase, and CDK1 in G2 and mitosis. Once bound with cyclin, CDKs require phosphorylation to function. This is performed by the cell division cycle phosphatases (see below). Once activated, CDKs are involved in activating a downstream chain of proteins which promote progression through the cell cycle. CDKs are usually present in the cell at similar concentrations throughout the entire cell cycle, relying on cyclins to become active.
Cyclins are small molecules which attach to the various CDK molecules to allow them to act. These molecules are produced by the cell to promote progression through the cell cycle, and there are several types:
- D-Cyclins are not present during G0, but become activated when the cell receives signals to divide. They bind to CDK 4 and CDK 6 and promote progressions through G1.
- E-Cyclins become active at the end of G1 and bind to CDK 2. They are important for progression from G1 to S phase. The E-CDK2 complex is degraded by the SPC ubiquitin ligase during S-phase.
- α-cyclins bind with both CDK 1 and 2. The α-CDK2 complex is required to progress through S phase. The α-CDK1 complex promotes progression through G2 phase, and is thought to promote chromatin condensation. This complex is destroyed by APC (anaphase promoting complex) in the prometaphase.
- β-cyclins bind with CDK 1. The resulting complex becomes active during the prophase stage of mitosis. It is involved in centromere separation as well as other mitotic events. Once activated, the β–CDK1 complex also inactivates the molecules which inhibit its expression, allowing a large amount of β–CDK1 to become active quickly. β –CDK1 is also destroyed by the anaphase promoting complex (APC).
Cell Division Cycle Phosphatases (CDC)
In humans, there are multiple types of Cell Division Cycle Phosphatases (cdc) that are relevant for control of the cell cycle. Three important molecules include cdc25A, cdc25B and cdc25C. They function by removing phosphate groups from the various cyclin/CDK complexes, allowing them to become active. They are important targets for control of the cell cycle, as their removal will render the CDK complexes inactive despite the presence of cyclin.
Cyclin Dependent Kinase Inhibitors (CDKI)
This is a group of kinases which (in general) inhibit the production or function of the CDKs. There are two major families:
- The INK4 group of CDKIs consist of four proteins which inhibit the binding of cyclin D to CDK 4 and 6.
- The CIP/KIP group of proteins bind to and inhibit the function of cyclin-E/CDK2 and cyclin-α/CDK2 complexes. An important member of this group is p21, which in turn is activated by p53 (below).
Retinoblastoma Protein 1 (RB1)
The RB1 gene was first identified in children with familial retinoblastoma. Its protein functions as a tumour suppressor gene by binding to and thereby inhibiting a family of proteins known as E2F. These proteins promote the production of cyclins (E and α) as well as DNA replication proteins. Rb normally exists bound to E2F; the cyclin-D/CDK4&6 and cyclin-E/CDK2 complexes cause phosphorylation of Rb and change its configuration, releasing the E2F protein which then leads to progression of the cell cycle.
Tumour Protein P53 (TP53)
TP53 is an important protein which helps to regulate many stages of the cell cycle. It is located at the centre of a number of pathways related to DNA repair, apoptosis, angiogenesis and cell cycle arrest. Two important activators are the ATM/CHK2 pathway (triggered by DNA damage) and the p19ARF pathway (triggered by oncogene activation). The loss of p53, a common occurrence in human tumours, leads to deregulation of the cell cycle. Li-Fraumeni syndrome, a genetic condition caused by mutation in the p53 gene, leads to multiple tumours developing throughout the body.