17.4 : Positive Regulator Molecules

The positive regulator molecules promote the transition through various stages of the cell cycle via the interaction of two protein groups: cyclins and cyclin-dependent kinases or Cdks.

Mammalian cells contain around nine Cdks, with four of them, Cdk1, Cdk6, Cdk4, and Cdk2, involved in the cell cycle.

The activity and specificity of any given Cdk depends on the binding of cyclins. Cyclins are grouped as G1, G1/S, S, or M phase cyclins, and their expression is specific to the stage they trigger

For instance, in the G1 phase, cyclin D binds to Cdk4 and Cdk6, promoting the cell to the late G1 phase.

Next, cyclin E accumulates and forms a complex with Cdk2. The cyclin E-Cdk2 complex, along with the cyclin D-Cdk4/6, triggers the G1 to S transition, which irreversibly commits the cells into the cycle.

At the start of S phase, cyclin-E remains elevated and bound to Cdk2. In addition, cyclin-A level rises and combines with Cdk2. Both the complexes are directly responsible for DNA replication.

Although cyclin E levels fall, cyclin-A levels are high throughout the S and G2-phases. At the G2-M transition, cyclin A levels drop and cyclin B levels rise.

Cyclin B combines with Cdk1, triggering the start of mitosis. The levels of mitotic cyclins fall mid-mitosis, thus inactivating the Cdk.

The inactive Cdk has a protein loop that blocks substrate protein access to the active site. It is only when a specific cyclin binds to the Cdk, that the loop moves away from the active site, thus partially activating Cdk.

The complete activation of the Cdk-cyclin complex depends on another enzyme called Cdk activating kinase or CAK.

The CAK phosphorylates an amino acid near the active site causing a conformational change in Cdk, enabling the Cdk-cyclin complex to phosphorylate its target proteins and induce specific cell cycle stage events.