Biology:CDC25A

Generic protein structure example

M-phase inducer phosphatase 1 also known as dual specificity phosphatase Cdc25A is a protein that in humans is encoded by the cell division cycle 25 homolog A (CDC25A) gene.

Function

CDC25A is a member of the CDC25 family of dual-specificity phosphatases.

Dual-specificity protein phosphatases remove phosphate groups from phosphorylated tyrosine and serine / threonine residues. They represent a subgroup of the tyrosine phosphatase family (as opposed to the serine/threonine phosphatase family).

All mammals examined to date have three homologues of the ancestral Cdc25 gene (found e.g. in the fungus species S. pombe), designated Cdc25A, Cdc25B, and Cdc25C. In contrast, some invertebrates harbour two (e.g., the Drosophila proteins String and Twine) or four (e.g., C. elegans Cdc-25.1 - Cdc-25.4) homologues. CDC25A is required for progression from G1 to the S phase of the cell cycle, but also plays roles in later cell cycle events. In particular, it is stabilized in metaphase cells and is degraded upon metaphase exit akin to Cyclin B. It is competent to activate the G1/S cyclin-dependent kinases CDK4 and CDK2 by removing inhibitory phosphate groups from adjacent tyrosine and threonine residues; it can also activate Cdc2 (Cdk1), the principal mitotic Cdk.

Involvement in cancer

CDC25A is specifically degraded in response to DNA damage, resulting in cell cycle arrest. Thus, this degradation represents one axis of a DNA damage checkpoint, complementing induction of p53 and p21 in the inhibition of CDKs. CDC25A is considered an oncogene, as it can cooperate with oncogenic RAS to transform rodent fibroblasts, and it is overexpressed in tumours from a variety of tissues, including breast and head & neck tumours. It is a target of the E2F family of transcription factors. Therefore, its overexpression is a common consequence of dysregulation of the p53-p21-Cdk axis in carcinogenesis.

Interactions

CDC25A has been shown to interact with:

• ASK1,
• C-Raf,
• CHEK1,
• CCNE1,
• EGFR,
• PIM1 and
• YWHAB.

External links

• Human CDC25A genome location and CDC25A gene details page in the UCSC Genome Browser.

Further reading

• Parsons R (1998). "Phosphatases and tumorigenesis". Current Opinion in Oncology 10 (1): 88–91. doi:10.1097/00001622-199801000-00014. PMID 9466490. 
• "Cell cycle targets of Ras/Raf signalling". Oncogene 17 (11 Reviews): 1457–62. 1998. doi:10.1038/sj.onc.1202185. PMID 9779991. 
• "Cell cycle regulation by the Cdc25 phosphatase family". Progress in Cell Cycle Research 4: 107–14. 2000. doi:10.1007/978-1-4615-4253-7_10. ISBN 978-1-4613-6909-7. PMID 10740819. 
• "Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins". Cell 67 (6): 1181–94. 1992. doi:10.1016/0092-8674(91)90294-9. PMID 1836978. 
• "14-3-3 proteins associate with cdc25 phosphatases". Proc. Natl. Acad. Sci. U.S.A. 92 (17): 7892–6. 1995. doi:10.1073/pnas.92.17.7892. PMID 7644510. Bibcode: 1995PNAS...92.7892C. 
• "CDC25 phosphatases as potential human oncogenes". Science 269 (5230): 1575–7. 1995. doi:10.1126/science.7667636. PMID 7667636. Bibcode: 1995Sci...269.1575G. 
• "Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation". Genes Dev. 9 (9): 1046–58. 1995. doi:10.1101/gad.9.9.1046. PMID 7744247. http://repository.cshl.edu/30592/1/Genes%20Dev.-1995-Galaktionov-1046-58.pdf. 
• "Chromosome mapping of human CDC25A and CDC25B phosphatases". Genomics 18 (1): 144–7. 1994. doi:10.1006/geno.1993.1440. PMID 8276402. 
• "Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25". J. Biol. Chem. 271 (9): 5118–24. 1996. doi:10.1074/jbc.271.9.5118. PMID 8617791. 
• "Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest". Mol. Cell. Biol. 16 (7): 3934–44. 1996. doi:10.1128/mcb.16.7.3934. PMID 8668211. 
• "Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis". Cancer Res. 57 (14): 2974–8. 1997. PMID 9230211. 
• "Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A". Cell 93 (4): 617–25. 1998. doi:10.1016/S0092-8674(00)81190-3. PMID 9604936. 
• "The mammalian Cut homeodomain protein functions as a cell-cycle-dependent transcriptional repressor which downmodulates p21WAF1/CIP1/SDI1 in S phase". EMBO J. 17 (16): 4680–94. 1998. doi:10.1093/emboj/17.16.4680. PMID 9707427. 
• "E2F and Histone Deacetylase Mediate Transforming Growth Factor β Repression of cdc25A during Keratinocyte Cell Cycle Arrest". Mol. Cell. Biol. 19 (1): 916–22. 1999. doi:10.1128/mcb.19.1.916. PMID 9858615. 
• "A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2". Oncogene 18 (3): 573–82. 1999. doi:10.1038/sj.onc.1202362. PMID 9989807. 
• "Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway". J. Biol. Chem. 274 (26): 18659–66. 1999. doi:10.1074/jbc.274.26.18659. PMID 10373478. 
• "Tyrosine Phosphorylation of the Proto-Oncoprotein Raf-1 Is Regulated by Raf-1 Itself and the Phosphatase Cdc25A". Mol. Cell. Biol. 19 (7): 4819–24. 1999. doi:10.1128/mcb.19.7.4819. PMID 10373531. 
• "CDC25A Phosphatase Is a Target of E2F and Is Required for Efficient E2F-Induced S Phase". Mol. Cell. Biol. 19 (9): 6379–95. 1999. doi:10.1128/mcb.19.9.6379. PMID 10454584.