CDK4

Cyclin-Dependent Kinase 4 (CDK4)

Cyclin-Dependent Kinase 4 (CDK4) is a protein kinase that is crucial in the regulation of the cell cycle. It is a member of the cyclin-dependent kinase family, which is involved in the control of cell division and proliferation. CDK4, in particular, plays a significant role in the transition from the G1 phase to the S phase of the cell cycle.

Structure and Function

CDK4 is a serine/threonine kinase that requires association with a regulatory subunit, known as a cyclin, to become active. The primary cyclin partner for CDK4 is Cyclin D, and together they form the CDK4/cyclin D complex. This complex is responsible for phosphorylating the Retinoblastoma protein (Rb), leading to the release of E2F transcription factors and the subsequent progression of the cell cycle into the S phase.

Regulation

The activity of CDK4 is tightly regulated by various mechanisms:

• Cyclin Binding: CDK4 is activated upon binding to cyclin D, which is synthesized in response to growth signals.
• Phosphorylation: CDK4 can be phosphorylated by Cyclin-Dependent Kinase Activating Kinase (CAK), which is necessary for its full activation.
• Inhibition by CDK Inhibitors: CDK4 activity can be inhibited by CDK inhibitors such as p16^INK4a, which bind to CDK4 and prevent its association with cyclin D.

Clinical Significance

CDK4 is implicated in various cancers due to its role in cell cycle regulation. Overexpression or amplification of CDK4 can lead to uncontrolled cell proliferation, a hallmark of cancer. CDK4 inhibitors, such as Palbociclib, have been developed as targeted therapies for cancers with dysregulated CDK4 activity.

Research and Therapeutic Implications

Research into CDK4 has led to the development of specific inhibitors that are used in cancer therapy. These inhibitors are particularly effective in cancers where the CDK4 pathway is aberrantly activated. Ongoing research aims to better understand the role of CDK4 in normal and cancerous cells, as well as to develop more effective therapeutic strategies.

Also see

• Cell Cycle
• Cyclin D
• Retinoblastoma protein
• Cyclin-Dependent Kinase Inhibitors
• Palbociclib