Cyclin-Dependent Kinases (CDKs) are enzymes that regulate the cell cycle. They orchestrate the precise sequence of events allowing a cell to grow, duplicate its genetic material, and divide. Present in all eukaryotes, CDKs ensure accurate cell division.
The Cell Cycle: A Fundamental Process
The cell cycle is a controlled series of events culminating in cell division, enabling growth and tissue repair. It divides into two main stages: interphase and the M phase. Interphase, the preparatory stage, consists of three phases: G1, S, and G2.
During G1 phase, the cell grows and synthesizes proteins and organelles for DNA replication. In S phase, the cell’s DNA is replicated. G2 phase involves further growth and protein synthesis as the cell prepares for mitosis. The M phase encompasses mitosis, where the nucleus divides, and cytokinesis, where the cytoplasm separates to form two daughter cells.
CDKs: The Cell Cycle’s Essential Enzymes
CDKs are serine/threonine protein kinases. They function by adding phosphate groups to target proteins, a process called phosphorylation, which activates or inactivates the protein. CDKs are largely inactive on their own; they must bind to a regulatory protein called a cyclin to become functional.
Once a cyclin binds to a CDK, it changes the CDK’s shape, making its active site accessible for phosphorylating target proteins. Cyclins have no enzymatic activity but are necessary to activate their CDK counterparts. This complex formation is required for their kinase activity and cell cycle regulation.
How CDKs Drive Cell Cycle Progression
Different cyclin-CDK complexes activate at specific times, driving the cell through each phase. These complexes phosphorylate proteins, initiating stage-specific events.
In G1 phase, Cyclin D partners with CDK4 and CDK6 to prepare the cell for DNA synthesis. These G1-CDK complexes phosphorylate the retinoblastoma protein (Rb), a tumor suppressor. Rb phosphorylation releases transcription factors, allowing gene expression for S phase entry.
As the cell progresses, Cyclin E associates with CDK2, promoting the G1-S transition and initiating DNA replication. During S phase, Cyclin A binds to CDK2, supporting DNA synthesis by phosphorylating replication proteins. For M phase entry, Cyclin B forms a complex with CDK1. This M-CDK complex triggers cell division changes, such as chromosome condensation and nuclear envelope breakdown, by phosphorylating mitotic proteins.
Maintaining Control: Regulation of CDK Activity
CDK activity is strictly regulated through several mechanisms. One mechanism involves inhibitory phosphorylation, where phosphate groups are added to specific CDK sites, temporarily inactivating it. Kinases like Wee1 and Myt1 add these phosphates, while phosphatases like Cdc25 remove them, allowing CDK activation.
Another control mechanism involves CDK inhibitors (CKIs), proteins that reduce CDK activity. These inhibitors, such as p16, p21, and p27, bind directly to CDK-cyclin complexes, preventing target protein phosphorylation. For example, p16 specifically inhibits CDK4 and CDK6, while p21 and p27 inhibit a broader range of CDK-cyclin complexes.
The cell also regulates CDK activity through protein degradation, particularly the destruction of cyclins. As cyclins degrade, their associated CDKs become inactive, allowing the cell cycle to progress or exit. Cell cycle checkpoints are monitoring systems that halt progression if errors, such as DNA damage or incomplete DNA replication, are detected. These checkpoints modulate CDK activity, ensuring the cell does not divide until all conditions are met.
CDKs and Their Role in Health and Disease
Careful CDK regulation is vital for normal cellular function; disruptions can have consequences. Uncontrolled cell division, a hallmark of cancer, often results from CDK dysregulation. In many cancers, CDKs become overactive or their natural inhibitors non-functional, leading to unchecked cell proliferation.
CDKs are targets for cancer therapies due to their role in promoting cell growth and division. Specific CDK inhibitors have been developed to block these enzymes. For example, CDK4/6 inhibitors treat certain breast cancers by halting the cell cycle and preventing cancer cell proliferation. These targeted therapies restore control to the dysregulated cell cycle in cancer.