Cdc25

Function in activating Cdk1

Cdc25 activates cyclin dependent kinases by removing phosphate from residues in the Cdk active site. In turn, the phosphorylation by M-Cdk (a complex of Cdk1 and cyclin B) activates Cdc25. Together with Wee1, M-Cdk activation is switch-like. The switch-like behavior forces entry into mitosis to be quick and irreversible. Cdk activity can be reactivated after dephosphorylation by Cdc25. The Cdc25 enzymes Cdc25A-C are known to control the transitions from G1 to S phase and G2 to M phase.

Structure

The structure of Cdc25 proteins can be divided into two main regions: the N-terminal region, which is highly divergent and contains sites for its phosphorylation and ubiquitination, which regulate the phosphatase activity; and the C-terminal region, which is highly homologous and contains the catalytic site.

Evolution and species distribution

Cdc25 enzymes are well conserved through evolution, and have been isolated from fungi such as yeasts as well as all metazoans examined to date, including humans. The exception among eukaryotes may be plants, as the purported plant Cdc25s have characteristics, (such as the use of cations for catalysis), that are more akin to serine/threonine phosphatases than dual-specificity phosphatases, raising doubts as to their authenticity as Cdc25 phosphatases. The Cdc25 family appears to have expanded in relation to the complexity of the cell-cycle and life-cycle of higher animals. Yeasts have a single Cdc25 (as well as a distantly related enzyme known as Itsy-bitsy phosphatase 1, or Ibp1). Drosophila melanogaster has two Cdc25s, known as string and twine, which control mitosis and meiosis, respectively. Most other model organisms examined have three Cdc25s, designated Cdc25A, Cdc25B, and Cdc25C. An exception is the nematode Caenorhabditis elegans, which has four distinct Cdc25 genes (Cdc-25.1 to Cdc-25.4).

Knockout models

Although the highly conserved nature of the Cdc25s implies an important role in cell physiology, Cdc25B and Cdc25C knockout mice (both single and double mutants) are viable and display no major alterations in their cell cycles, suggesting some functional compensation either via other Cdk regulatory enzymes (such as Wee1 and Myt1) or from the activity of the third member of the family, Cdc25A. Hiroaki Kiyokawa's laboratory has shown that Cdc25A knockout mice are not viable.

In human disease

The Cdc25s, and in particular Cdc25A and Cdc25B, are proto-oncogenes in humans and have been shown to be overexpressed in a number of cancers. The central role of Cdc25s in the cell cycle has garnered them considerable attention from the pharmaceutical industry as potential targets for novel chemotherapeutic (anti-cancer) agents. To date, no clinically viable compounds targeting these enzymes have been described.

A large number of potent small-molecule Cdc25 Inhibitors have been identified that bind to the active site and belong to various chemical classes, including natural products, lipophilic acids, quinonoids, electrophiles, sulfonylated aminothiazoles and phosphate bioisosteres. Although some progress has been made in developing potent and selective inhibitors for Cdc25 family of proteins, there is scope for development of novel therapeutic strategies to target them. A new class of peptide-derived inhibitors, based on sequence homology with the protein substrate, can be developed. It is challenging to use these compounds as drugs due to their lack of suitable ADME properties.

References

References

1. Boutros, R., Lobjois, V. & Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets?. Nat Rev Cancer 7, 495–507 (2007). https://doi.org/10.1038/nrc2169
2. (May 1991). "Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein". Nature.
3. Morgan, David. The Cell Cycle: Principles of Control. London: New Science Press, 2007. 96-98, 34-35. Print.
4. "Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents".
5. (July 1990). "Human homolog of fission yeast cdc25 mitotic inducer is expressed predominantly in G2". Proc. Natl. Acad. Sci. U.S.A..
6. (September 2004). "A small CDC25 dual-specificity tyrosine-phosphatase isoform in Arabidopsis thaliana". Proc. Natl. Acad. Sci. U.S.A..
7. (April 1989). "Genetic Control of Cell Division Patterns in the Drosophila Embryo". Cell.
8. (June 1992). "twine, a cdc25 homolog that functions in the male and female germline of Drosophila". Cell.
9. (July 1998). "The four cdc25 genes from the nematode Caenorhabditis elegans". Gene.
10. (April 2005). "Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein Phosphatases". Mol. Cell. Biol..
11. (August 2004). "Cdc25 phosphatases and cancer". Chem. Biol..