Cdc25
Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle". Dual-specificity phosphatases are considered a sub-class of protein tyrosine phosphatases. By removing inhibitory phosphate residues from target Cyclin-Dependent Kinases (Cdks),[1] Cdc25 proteins control entry into and progression through various phases of the cell cycle, including mitosis and S ("Synthesis") phase.
Function of Cdc25 in Activating Cdk1
Cdc25 activates cyclin dependent kinases by removing phosphate from residues in the Cdk active site. Also, the phosphorylation of 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.[2]
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.[3]
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.[4] 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.[5] 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[6] and meiosis,[7] 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).[8]
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,[9] 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.
Cdc25s 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.[10] 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.[3] 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, electrophilies, sulfonylated aminothiazoles and phosphate bioisosteres.[3] 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.[3]
References
- ↑ Strausfeld U, Labbé JC, Fesquet D, et al. (May 1991). "Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein". Nature. 351 (6323): 242–5. doi:10.1038/351242a0. PMID 1828290.
- ↑ Morgan, David. The Cell Cycle: Principles of Control. London: New Science Press, 2007. 96-98, 34-35. Print.
- 1 2 3 4 Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents
- ↑ Sadhu K, Reed SI, Richardson H, Russell P (July 1990). "Human homolog of fission yeast cdc25 mitotic inducer is expressed predominantly in G2". Proc. Natl. Acad. Sci. U.S.A. 87 (13): 5139–43. doi:10.1073/pnas.87.13.5139. PMC 54277
. PMID 2195549. - ↑ Landrieu I, da Costa M, De Veylder L, et al. (September 2004). "A small CDC25 dual-specificity tyrosine-phosphatase isoform in Arabidopsis thaliana". Proc. Natl. Acad. Sci. U.S.A. 101 (36): 13380–5. doi:10.1073/pnas.0405248101. PMC 516575. PMID 15329414.
- ↑ Edgar BA, O'Farrell PH (April 1989). "Genetic Control of Cell Division Patterns in the Drosophila Embryo". Cell. 57 (1): 177–87. doi:10.1016/0092-8674(89)90183-9. PMC 2755076. PMID 2702688.
- ↑ Alphey L, Jimenez J, White-Cooper H, Dawson I, Nurse P, Glover DM (June 1992). "twine, a cdc25 homolog that functions in the male and female germline of Drosophila". Cell. 69 (6): 977–88. doi:10.1016/0092-8674(92)90616-K. PMID 1606618.
- ↑ Ashcroft NR, Kosinski ME, Wickramasinghe D, Donovan PJ, Golden A (July 1998). "The four cdc25 genes from the nematode Caenorhabditis elegans". Gene. 214 (1–2): 59–66. doi:10.1016/S0378-1119(98)00228-5. PMID 9651482.
- ↑ Ferguson AM, White LS, Donovan PJ, Piwnica-Worms H (April 2005). "Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein Phosphatases". Mol. Cell. Biol. 25 (7): 2853–60. doi:10.1128/MCB.25.7.2853-2860.2005. PMC 1061644. PMID 15767688.
- ↑ Kristjánsdóttir K, Rudolph J (August 2004). "Cdc25 phosphatases and cancer". Chem. Biol. 11 (8): 1043–51. doi:10.1016/j.chembiol.2004.07.007. PMID 15324805.