CDC25A
Protein-coding gene in humans
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 Drosophila C. elegans 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 .[ 5]
Interactions
CDC25A has been shown to interact with:
References
^ a b c GRCh38: Ensembl release 89: ENSG00000164045 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032477 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Entrez Gene: CDC25A cell division cycle 25 homolog A (S. pombe)" .^ Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H (Jul 2001). "The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1" . Mol. Cell. Biol . 21 (14): 4818–28. doi :10.1128/MCB.21.14.4818-4828.2001 . PMC 87174 PMID 11416155 . ^ Galaktionov K, Jessus C, Beach D (May 1995). "Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation" (PDF) . Genes Dev . 9 (9): 1046–58. doi :10.1101/gad.9.9.1046 PMID 7744247 . ^ Huang TS, Shu CH, Yang WK, Whang-Peng J (Jul 1997). "Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis". Cancer Res . 57 (14): 2974–8. PMID 9230211 . ^ Goloudina A, Yamaguchi H, Chervyakova DB, Appella E, Fornace AJ, Bulavin DV (2003). "Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint" . Cell Cycle . 2 (5): 473–8. doi :10.4161/cc.2.5.482 PMID 12963847 . ^ Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (Sep 1997). "Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25". Science . 277 (5331): 1497–501. doi :10.1126/science.277.5331.1497 . PMID 9278511 . ^ Zhao H, Watkins JL, Piwnica-Worms H (Nov 2002). "Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints" . Proc. Natl. Acad. Sci. U.S.A . 99 (23): 14795–800. Bibcode :2002PNAS...9914795Z . doi :10.1073/pnas.182557299 PMC 137498 PMID 12399544 . ^ Jin J, Ang XL, Ye X, Livingstone M, Harper JW (Jul 2008). "Differential roles for checkpoint kinases in DNA damage-dependent degradation of the Cdc25A protein phosphatase" . J. Biol. Chem . 283 (28): 19322–8. doi :10.1074/jbc.M802474200 PMC 2443656 PMID 18480045 . ^ Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (Feb 1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest" . Mol. Cell. Biol . 19 (2): 1460–9. doi :10.1128/mcb.19.2.1460 . PMC 116074 PMID 9891079 . ^ Xu X, Burke SP (Mar 1996). "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. doi :10.1074/jbc.271.9.5118 PMID 8617791 . ^ Wang Z, Wang M, Lazo JS, Carr BI (May 2002). "Identification of epidermal growth factor receptor as a target of Cdc25A protein phosphatase" . J. Biol. Chem . 277 (22): 19470–5. doi :10.1074/jbc.M201097200 PMID 11912208 . ^ Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y (Jun 1999). "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. doi :10.1074/jbc.274.26.18659 PMID 10373478 . ^ Conklin DS, Galaktionov K, Beach D (Aug 1995). "14-3-3 proteins associate with cdc25 phosphatases" . Proc. Natl. Acad. Sci. U.S.A . 92 (17): 7892–6. Bibcode :1995PNAS...92.7892C . doi :10.1073/pnas.92.17.7892 PMC 41252 PMID 7644510 .
External links
Further reading
Parsons R (1998). "Phosphatases and tumorigenesis". Current Opinion in Oncology . 10 (1): 88–91. doi :10.1097/00001622-199801000-00014 . PMID 9466490 . S2CID 33899887 . Kerkhoff E, Rapp UR (1998). "Cell cycle targets of Ras/Raf signalling". Oncogene . 17 (11 Reviews): 1457–62. doi :10.1038/sj.onc.1202185 . PMID 9779991 . S2CID 19673633 . Nilsson I, Hoffmann I (2000). "Cell cycle regulation by the Cdc25 phosphatase family". Progress in Cell Cycle Research . Vol. 4. pp. 107–14. doi :10.1007/978-1-4615-4253-7_10 . ISBN 978-1-4613-6909-7 PMID 10740819 . Galaktionov K, Beach D (1992). "Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins". Cell . 67 (6): 1181–94. doi :10.1016/0092-8674(91)90294-9 . PMID 1836978 . S2CID 9659637 . Conklin DS, Galaktionov K, Beach D (1995). "14-3-3 proteins associate with cdc25 phosphatases" . Proc. Natl. Acad. Sci. U.S.A . 92 (17): 7892–6. Bibcode :1995PNAS...92.7892C . doi :10.1073/pnas.92.17.7892 PMC 41252 PMID 7644510 . Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M, Beach D (1995). "CDC25 phosphatases as potential human oncogenes". Science . 269 (5230): 1575–7. Bibcode :1995Sci...269.1575G . doi :10.1126/science.7667636 . PMID 7667636 . Galaktionov K, Jessus C, Beach D (1995). "Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation" (PDF) . Genes Dev . 9 (9): 1046–58. doi :10.1101/gad.9.9.1046 PMID 7744247 . Demetrick DJ, Beach DH (1994). "Chromosome mapping of human CDC25A and CDC25B phosphatases". Genomics . 18 (1): 144–7. doi :10.1006/geno.1993.1440 . PMID 8276402 . Xu X, Burke SP (1996). "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. doi :10.1074/jbc.271.9.5118 PMID 8617791 . Tiefenbrun N, Melamed D, Levy N, Resnitzky D, Hoffman I, Reed SI, Kimchi A (1996). "Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest" . Mol. Cell. Biol . 16 (7): 3934–44. doi :10.1128/mcb.16.7.3934 . PMC 231390 PMID 8668211 . Huang TS, Shu CH, Yang WK, Whang-Peng J (1997). "Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis". Cancer Res . 57 (14): 2974–8. PMID 9230211 . Fauman EB, Cogswell JP, Lovejoy B, Rocque WJ, Holmes W, Montana VG, Piwnica-Worms H, Rink MJ, Saper MA (1998). "Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A" . Cell . 93 (4): 617–25. doi :10.1016/S0092-8674(00)81190-3 PMID 9604936 . S2CID 5762201 . Coqueret O, Bérubé G, Nepveu A (1998). "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. doi :10.1093/emboj/17.16.4680 . PMC 1170797 PMID 9707427 . Iavarone A, Massagué J (1999). "E2F and Histone Deacetylase Mediate Transforming Growth Factor β Repression of cdc25A during Keratinocyte Cell Cycle Arrest" . Mol. Cell. Biol . 19 (1): 916–22. doi :10.1128/mcb.19.1.916 . PMC 83949 PMID 9858615 . Sexl V, Diehl JA, Sherr CJ, Ashmun R, Beach D, Roussel MF (1999). "A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2" . Oncogene . 18 (3): 573–82. doi :10.1038/sj.onc.1202362 PMID 9989807 . Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y (1999). "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. doi :10.1074/jbc.274.26.18659 PMID 10373478 . Xia K, Lee RS, Narsimhan RP, Mukhopadhyay NK, Neel BG, Roberts TM (1999). "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. doi :10.1128/mcb.19.7.4819 . PMC 84280 PMID 10373531 . Vigo E, Müller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC, Helin K (1999). "CDC25A Phosphatase Is a Target of E2F and Is Required for Efficient E2F-Induced S Phase" . Mol. Cell. Biol . 19 (9): 6379–95. doi :10.1128/mcb.19.9.6379 . PMC 84608 PMID 10454584 .
