Inhibition of Cdk Activity

During cell cycle transitions, Cdk activity is regulated by multiple proteins, ensuring controlled cell growth, complete DNA replication, and mitotic distribution of the chromosomes to daughter cells.

In the absence of regulatory proteins, an abnormal cell goes unchecked, leading to conditions such as cancer.

In a normal cell, Cdk activity is regulated through multiple mechanisms including cyclin degradation, inhibitory phosphorylation, and inhibitory conformational changes induced by Cdk inhibitor binding.

Cyclin levels are known to fluctuate during the cell cycle. Cdks are only active when bound to cyclin, therefore, cyclin degradation leaves Cdks inactive and unable to promote the transition to the next cell cycle stage.

In another mechanism, a kinase named Wee1, phosphorylates the active site in Cdk.  This phosphorylation inhibits the activity of the cyclin-Cdk complex.

Additionally, Cdk inhibitors or CKIs, such as p16, p21, and p27, regulate Cdk activity through inhibitory conformational changes.

For instance, if DNA damage occurs during G1, p16 interacts with the cyclin-Cdk complex. This interaction causes a large structural rearrangement, detaching the bound cyclin, causing Cdk inactivation. 

DNA damage in the G1 phase can also trigger the tumor suppressor protein, p53, to activate p21.

G1/S-Cdk and S-Cdk complexes are bound and inhibited by p21, arresting the cells in the G1 phase, and allowing enough time for DNA repair.

For the G1/S phase transition to take place, the cell is required to have all the resources needed for DNA replication. If the cell lacks the necessary resources, p27 binds to G1/S-Cdk and S-Cdk complexes, inhibiting the enzyme activity.

Once favorable conditions for cell cycle progression are met, p27 is degraded, restoring Cdk activity and promoting cell transition.