CDKs

CDKs, or cyclin-dependent kinases, are a family of serine/threonine kinases that regulate cell cycle progression and certain transcriptional programs in eukaryotic cells. They require association with regulatory cyclins to become active, and their catalytic activity is further controlled by phosphorylation. Activation generally depends on phosphorylation of a T-loop by a CDK-activating kinase, which relieves autoinhibition. Inhibitory phosphorylation by WEE1 and subsequent dephosphorylation by Cdc25 also modulate activity. CDK activity is finely tuned by CDK inhibitors (CKIs) such as p21, p27, and p16, which can block kinase activity or prevent cyclin binding.

CDKs function in a series of cyclin-dependent events that drive the cell cycle. In mammals, cyclin D–CDK4/6 activity promotes progression through early G1, followed by cyclin E/A–CDK2 activity to drive the G1/S transition and S-phase progression. Cyclin A–CDK2 supports S phase, and cyclin B–CDK1 governs the G2/M transition and mitosis. Phosphorylation of the retinoblastoma (RB) protein by these complexes leads to the release of E2F transcription factors, enabling transcription of S-phase genes. CDKs also influence centrosome function, chromosome condensation, and mitotic spindle dynamics.

Beyond cell cycle control, several CDKs participate in transcriptional regulation. CDK7, a component of TFIIH, and CDK9, CDK12, and CDK13 phosphorylate RNA polymerase II or associated factors to regulate transcription initiation and elongation, as well as RNA processing.

Clinical relevance centers on dysregulated CDK activity in cancer. CDK inhibitors, notably selective CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib, are approved for certain hormone receptor–positive breast cancers. Resistance and toxicity remain areas of ongoing research, with combination strategies under investigation.