Cdc25
Encyclopedia
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 Kinase
s (Cdks), Cdc25 proteins control entry into and progression through various phases of the cell cycle
, including mitosis
and S ("Synthesis") phase.
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 phosphorylation by Cdc25. The Cdc25 enzymes Cdc25A-C are known to control the transitions from G1 to S phase and G2 to M phase.
s as well as all metazoans examined to date, including humans. The exception among eukaryotes may be plant
s, 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 phosphatase
s, 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).
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.
s. 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, electrophilies, 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.
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
first isolated from the yeast Schizosaccharomyces pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
as a cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4
CDC4
CDC4 may refer to:* Cell division control protein 4* Saint-Quentin Aerodrome...
, 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 Kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
s (Cdks), Cdc25 proteins control entry into and progression through various phases of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
, including mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
and S ("Synthesis") phase.
Function of Cdc25 in Activating Cdk1
Cdc25 activates cyclin dependent kinases by the removal of phosphates from residues in the Cdk active site. Also, the phosphorylation of M-Cdk (a complex of Cdk1Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....
and cyclin B
Cyclin B
Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of 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 phosphorylation 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 yeastYeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
s as well as all metazoans examined to date, including humans. The exception among eukaryotes may be plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s, 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 phosphatase
Dual-specificity phosphatase
Dual-specificity phosphatase is a form of phosphatase that can act upon tyrosine or serine/threonine residues.-References:...
s, 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
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
has two Cdc25s, known as string and twine, which control mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
and meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
, respectively. Most other model organisms examined have three Cdc25s, designated Cdc25A, Cdc25B, and Cdc25C
CDC25C
M-phase inducer phosphatase 3 is an enzyme that in humans is encoded by the CDC25C gene.-Interactions:CDC25C has been shown to interact with MAPK14, CHEK1, PCNA, PIN1, PLK3 and NEDD4.-Further reading:...
. An exception is the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, 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 Wee1Wee1
Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe . It has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression....
and Myt1
MYT1
Myelin transcription factor 1 is a protein that in humans is encoded by the MYT1 gene.- External links :...
) 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 cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s. 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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
) 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, electrophilies, 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.
See also
- CyclinCyclinCyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
- Cell CycleCell CycleCell Cycle is a peer-reviewed scientific journal covering cell biology. The editor-in-chief is Mikhail V. Blagosklonny . Cell Cycle is abstracted and indexed in Medline/PubMed and the Science Citation Index Expanded....
- Cyclin-dependent kinaseCyclin-dependent kinasethumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
- Wee1Wee1Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe . It has a molecular mass of 96 kDa and it is a key regulator of cell cycle progression....