| |  |
| |
| | Domains of different isoforms of CDC25A (A1 and A2). The splice variant A2 lacks an in-frame exon (exon 6) encoding 40 amino acids (amino acid 143-182), however, have the same N- and C-termini compared to isoform A1. The approx. molecular weight of each isoform is mentioned in parenthesis. |
| |
| Description | The full length CDC25A protein consists of 524 amino acids with an estimated molecular weight of 59 kDa. The other reported isoform CDC25A2, consists of 484 amino acids with a molecular weight of 54.4 kDa. Both the isoforms have the same N- and C-terminal end, thus expected to have similar catalytic activity. The N-terminal regulatory domain contains several phosphorylation sites and show low sequence homology between CDC25 family members, whereas C-terminal end has conserved Rhodanese homology domain containing the active site cysteine. The catalytic site contain the CX5R motif (C= cysteine; X= any amino acid; R= arginine) common to all protein tyrosine phosphatases. |
| Expression | CDC25A is expressed early during embryonic stages and in adults it is expressed in a variety of normal cells and tissues. CDC25A is a highly expressed gene in a variety of human cancers including breast, esophageal, gastric, lung, thyroid, head and neck cancers and also in high grade lymphomas. |
| Localisation | CDC25A initially believed to be a nuclear protein. But using fluorescence loss in photobleaching (FLIP) the more dynamic nuclear-cytosolic shuttling of CDC25A localization have been reported. At the very N-terminus end between amino acid 38-59, the nuclear export sequence (NES) is located, whereas between amino acid 272-294, a bipartite nuclear localization signal (NLS) proved to be important for its nuclear localization. |
| Function | - It is a member of the M-phase inducer (MPI) phosphatase family protein, which not only regulates mitotic progression by activating mitotic CDKs in a dosage-dependent manner, it is also equally important for G1 to S-phase transition.
- During G1 to S transition, it activates CDK2 by removing two inhibitory phosphates on residues threonine 14 and tyrosine 15. During G2/M transition CDC25A similarly regulates the activity of CDK1 (CDC2).
- It is an important checkpoint protein in response to damage by ionizing radiation (IR), ultraviolet light (UV), replication inhibitor and by various DNA damaging agents. In response to DNA damage, CDC25A undergoes CHK1/CHK2-mediated phosphorylation followed by ubiquitination-dependent degradation leading to growth arrest in a p53-independent manner.
- CDC25A is essential for early embryonic development as Cdc25A-null mice die in utero by embryonic day 7.
- CDC25A is overexpressed in a variety of human cancers including breast, esophageal, gastric, lung, thyroid, head and neck cancers and lymphomas. CDC25A overexpression at least in breast cancer is mainly due to post-translation stabilization as oppose to gene amplification or transcriptional upregulation.
- CDC25A protein level is important for oncogene-induced transformation and mouse mammary tumor virus (MMTV)-neu/ras induced mammary tumorigenesis.
- During early cell cycle progression glycogen synthase kinase 3-beta (GSK-3β) can phosphorylate and degrade CDC25A, thus maintain the lower cellular levels of CDC25A. Interestingly, the same report showed that overproduction of CDC25A in human cancers is correlated to the inactivation of GSK-3β.
- It is an inhibitor of apoptosis by inhibiting apoptosis signal-regulating kinase 1 (ASK1).
- CDC25A plays an important role in spermatogenesis as decreased transcript level of Cdc25A is correlated with spermatogenic failure and failed sperm retrieval in infertile men. |
| Homology | CDC25A gene is highly conserved among mammals (99% homology with Chimpanzee; 90% with dog; about 86% with rat and about 85% with mouse). In mammals, CDC25A has two orthologs, CDC25B and CDC25C. Among them, the N-terminal regulatory region show low sequence homology (20-25% identity), however, the C-terminal catalytic region is quite conserved with about 64% homology with CDC25B and about 58% homology to CDC25C. |
| Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. |
| Galaktionov K, Beach D |
| Cell. 1991 ; 67 (6) : 1181-1194. |
| PMID 1836978 |
| |
| Chromosome mapping of human CDC25A and CDC25B phosphatases. |
| Demetrick DJ, Beach DH |
| Genomics. 1993 ; 18 (1) : 144-147. |
| PMID 8276402 |
| |
| Rapid destruction of human Cdc25A in response to DNA damage. |
| Mailand N, Falck J, Lukas C, Syljuˆ¢sen RG, Welcker M, Bartek J, Lukas J |
| Science (New York, N.Y.). 2000 ; 288 (5470) : 1425-1429. |
| PMID 10827953 |
| |
| Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C. |
| Wegener S, Hampe W, Herrmann D, Schaller HC |
| European journal of cell biology. 2000 ; 79 (11) : 810-815. |
| PMID 11139144 |
| |
| Mammalian G1- and S-phase checkpoints in response to DNA damage. |
| Bartek J, Lukas J |
| Current opinion in cell biology. 2001 ; 13 (6) : 738-747. |
| PMID 11698191 |
| |
| Involvement of Cdc25A phosphatase in Hep3B hepatoma cell growth inhibition induced by novel K vitamin analogs. |
| Wang Z, Southwick EC, Wang M, Kar S, Rosi KS, Wilcox CS, Lazo JS, Carr BI |
| Cancer research. 2001 ; 61 (19) : 7211-7216. |
| PMID 11585757 |
| |
| The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1. |
| Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H |
| Molecular and cellular biology. 2001 ; 21 (14) : 4818-4828. |
| PMID 11416155 |
| |
| Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. |
| Mailand N, Podtelejnikov AV, Groth A, Mann M, Bartek J, Lukas J |
| The EMBO journal. 2002 ; 21 (21) : 5911-5920. |
| PMID 12411508 |
| |
| A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells. |
| Melkun E, Pilione M, Paulson RF |
| Blood. 2002 ; 100 (10) : 3804-3811. |
| PMID 12411323 |
| |
| Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines. |
| Lˆffler H, Syljuˆ€sen RG, Bartkova J, Worm J, Lukas J, Bartek J |
| Oncogene. 2003 ; 22 (50) : 8063-8071. |
| PMID 14603247 |
| |
| Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. |
| Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H |
| The Journal of biological chemistry. 2003 ; 278 (24) : 21767-21773. |
| PMID 12676925 |
| |
| Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. |
| Xu X, Yamamoto H, Sakon M, Yasui M, Ngan CY, Fukunaga H, Morita T, Ogawa M, Nagano H, Nakamori S, Sekimoto M, Matsuura N, Monden M |
| Clinical cancer research : an official journal of the American Association for Cancer Research. 2003 ; 9 (5) : 1764-1772. |
| PMID 12738732 |
| |
| Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import. |
| Kˆ§llstrˆm H, Lindqvist A, Pospisil V, Lundgren A, Rosenthal CK |
| Experimental cell research. 2005 ; 303 (1) : 89-100. |
| PMID 15572030 |
| |
| PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo. |
| Kar S, Wang M, Yao W, Michejda CJ, Carr BI |
| Molecular cancer therapeutics. 2006 ; 5 (6) : 1511-1519. |
| PMID 16818510 |
| |
| CDC25 phosphatases in cancer cells: key players? Good targets? |
| Boutros R, Lobjois V, Ducommun B |
| Nature reviews. Cancer. 2007 ; 7 (7) : 495-507. |
| PMID 17568790 |
| |
| CDC25A levels determine the balance of proliferation and checkpoint response. |
| Ray D, Kiyokawa H |
| Cell cycle (Georgetown, Tex.). 2007 ; 6 (24) : 3039-3042. |
| PMID 18073536 |
| |
| Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. |
| Ray D, Terao Y, Fuhrken PG, Ma ZQ, DeMayo FJ, Christov K, Heerema NA, Franks R, Tsai SY, Papoutsakis ET, Kiyokawa H |
| Cancer research. 2007 ; 67 (3) : 984-991. |
| PMID 17283130 |
| |
| Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice. |
| Ray D, Terao Y, Nimbalkar D, Hirai H, Osmundson EC, Zou X, Franks R, Christov K, Kiyokawa H |
| Cancer research. 2007 ; 67 (14) : 6605-6611. |
| PMID 17638870 |
| |
| GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. |
| Kang T, Wei Y, Honaker Y, Yamaguchi H, Appella E, Hung MC, Piwnica-Worms H |
| Cancer cell. 2008 ; 13 (1) : 36-47. |
| PMID 18167338 |
| |
| 2-Methoxyestradiol inhibits hepatocellular carcinoma cell growth by inhibiting Cdc25 and inducing cell cycle arrest and apoptosis. |
| Kar S, Wang M, Carr BI |
| Cancer chemotherapy and pharmacology. 2008. |
| PMID 18246350 |
| |
