cdc25

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.Morgan, David. The Cell Cycle: Principles of Control. London: New Science Press, 2007. 96-98, 34-35. Print.

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.{{Cite web |url=http://pharmaxchange.info/presentations/cdc25.html |title=Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer Agents |access-date=2010-03-11 |archive-url=https://web.archive.org/web/20160303231929/http://pharmaxchange.info/presentations/cdc25.html |archive-date=2016-03-03 |url-status=dead }}

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.{{cite journal |vauthors=Sadhu K, Reed SI, Richardson H, Russell P |title=Human homolog of fission yeast cdc25 mitotic inducer is expressed predominantly in G2 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue=13 |pages=5139–43 |date=July 1990 |pmid=2195549 |pmc=54277 |doi=10.1073/pnas.87.13.5139|doi-access=free }} 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.{{cite journal |vauthors=Landrieu I, da Costa M, De Veylder L |title=A small CDC25 dual-specificity tyrosine-phosphatase isoform in Arabidopsis thaliana |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=36 |pages=13380–5 |date=September 2004 |pmid=15329414 |pmc=516575 |doi=10.1073/pnas.0405248101 |bibcode=2004PNAS..10113380L |display-authors=etal|doi-access=free }} 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{{cite journal |vauthors=Edgar BA, O'Farrell PH |title=Genetic Control of Cell Division Patterns in the Drosophila Embryo |journal=Cell |volume=57 |issue=1 |pages=177–87 |date=April 1989 |pmid=2702688 |doi=10.1016/0092-8674(89)90183-9 |pmc=2755076}} and meiosis,{{cite journal |vauthors=Alphey L, Jimenez J, White-Cooper H, Dawson I, Nurse P, Glover DM |title=twine, a cdc25 homolog that functions in the male and female germline of Drosophila |journal=Cell |volume=69 |issue=6 |pages=977–88 |date=June 1992 |pmid=1606618 |doi=10.1016/0092-8674(92)90616-K|s2cid=29299686 }} 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).{{cite journal |vauthors=Ashcroft NR, Kosinski ME, Wickramasinghe D, Donovan PJ, Golden A |title=The four cdc25 genes from the nematode Caenorhabditis elegans |journal=Gene |volume=214 |issue=1–2 |pages=59–66 |date=July 1998 |pmid=9651482 |doi=10.1016/S0378-1119(98)00228-5 |url=https://zenodo.org/record/1260051 }}

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,{{cite journal |vauthors=Ferguson AM, White LS, Donovan PJ, Piwnica-Worms H |title=Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein Phosphatases |journal=Mol. Cell. Biol. |volume=25 |issue=7 |pages=2853–60 |date=April 2005 |pmid=15767688 |pmc=1061644 |doi=10.1128/MCB.25.7.2853-2860.2005 }} 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.

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.{{cite journal |vauthors=Kristjánsdóttir K, Rudolph J |title=Cdc25 phosphatases and cancer |journal=Chem. Biol. |volume=11 |issue=8 |pages=1043–51 |date=August 2004 |pmid=15324805 |doi=10.1016/j.chembiol.2004.07.007 |doi-access=free }} 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.

• Cyclin

{{reflist}}

• {{Gene|CDC25A}}
• {{PDB3|1C25}} Human cDc25A at PDB
• {{Gene|CDC25B}}
• {{Gene|CDC25C}}

{{Protein tyrosine phosphatases}}

{{Cell cycle proteins}}

Category:Enzymes

Category:Cell cycle

Category:Fungal proteins