Wee1

Cellcycleprotein Wee1

Wee1 is a protein kinase that plays a crucial role in the cell cycle by regulating the cell cycle checkpoint between the G2 phase and M phase. It primarily functions by phosphorylating the Cyclin-dependent kinase 1 (CDK1) (also known as Cdc2) in conjunction with cyclin B, inhibiting the CDK1/cyclin B complex. This inhibition is essential for preventing the cell from entering mitosis prematurely, allowing time for DNA repair mechanisms to correct any DNA damage that may have occurred during replication in the S phase. The activity of Wee1 is particularly important in the context of maintaining genomic stability and preventing the propagation of damaged DNA, which could lead to cancer.

Function

Wee1 exerts its inhibitory effect on the cell cycle primarily through the phosphorylation of CDK1 on a specific tyrosine residue (Tyr15 in humans). This modification reduces the kinase activity of the CDK1/cyclin B complex, delaying the onset of mitosis. The regulation of CDK1 by Wee1 is a critical control point within the cell cycle, ensuring that cells do not commence mitosis until they are fully prepared, with all DNA damage repaired and the cell adequately grown.

In addition to its role in G2/M transition, Wee1 has been implicated in the response to DNA damage. Upon DNA damage, several signal transduction pathways are activated, leading to an increase in Wee1 activity and a concomitant decrease in CDK1 activity. This process contributes to the activation of the G2/M checkpoint, halting cell cycle progression and allowing for DNA repair.

Regulation

The activity of Wee1 is tightly regulated by both phosphorylation and protein degradation. Phosphorylation can either enhance or inhibit Wee1 activity, depending on the specific site and context. For example, phosphorylation by Akt has been shown to inhibit Wee1, promoting cell cycle progression.

Protein degradation of Wee1, particularly through the ubiquitin-proteasome pathway, also plays a significant role in controlling its levels within the cell. The degradation of Wee1 is promoted during the transition from G2 to M phase, facilitating the activation of CDK1 and the onset of mitosis.

Clinical Significance

Given its pivotal role in cell cycle regulation, Wee1 has emerged as a potential target for cancer therapy. Inhibitors of Wee1 are being explored as a strategy to selectively target cancer cells. By inhibiting Wee1 in cancer cells, which often rely on Wee1 for survival due to an increased burden of DNA damage, it is possible to induce mitotic catastrophe and cell death. This approach is particularly attractive for treating cancers with defects in other DNA damage response pathways, such as those with mutations in the TP53 gene.

See Also

• Cell cycle
• Cyclin-dependent kinase
• DNA repair
• Mitosis
• Oncogene