Disease relevance of CDC25B

• These findings suggest that overexpression of CDC25B may favor development and progression and may be an indicator of malignant behavior of gastric carcinomas [1].
• By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas [2].
• Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma [2].
• The results indicate that high CDC25A and CDC25B expression is related to a worse prognosis in ovarian cancer patients [3].
• In this study, we investigated the effect of CDC25B overexpression on radiation-induced G2-M arrest and radiation sensitivity in esophageal cancer cells [4].

High impact information on CDC25B

• A dual-specificity phosphatase Cdc25B is an unstable protein and triggers p34(cdc2)/cyclin B activation in hamster BHK21 cells arrested with hydroxyurea [5].
• Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25 [6].
• CDC25B phosphatase plays a key role in controlling G2-M progression by dephosphorylating two inhibitory residues of CDC2 and also has been suggested to have an oncogenic property [4].
• Without radiation, CDC25B overexpression had little effect on cell cycle fractions or growth rate [4].
• Overexpression of CDC25B overrides radiation-induced G2-M arrest and results in increased apoptosis in esophageal cancer cells [4].

Biological context of CDC25B

• Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation [7].
• Serine 146 phosphorylation is proposed to be a key event in the regulation of the CDC25B function in the initiation of mammalian mitosis [8].
• Furthermore, serine-309 of CDC25B was sufficient to produce its cytoplasmic distribution with co-expression of 14-3-3beta, even when other putative 14-3-3 binding sites were mutated [9].
• Chromosome mapping of human CDC25A and CDC25B phosphatases [10].
• CDC25A and CDC25B, being oncogenes, are overexpressed in a variety of human malignancies [11].

Anatomical context of CDC25B

• Knockdown experiments by RNAi confirm that the centrosome phosphorylation of CDC25B on S353 depends on Aurora-A kinase [12].
• CDC25A and CDC25B cooperate with Ha-ras or loss of Rb1 in the oncogenic transformation of rodent fibroblasts [13].
• Reverse transcription-PCR assay indicated that CDC25B was overexpressed in tumor tissues relative to normal mucosa in 6 of 10 cases [14].
• Multivariate analysis indicated that CDC25B was an independent prognostic marker (risk ratio for death, 3.7; P < 0.0001) even after controlling for various factors such as lymph node metastasis, tumor size, degree of differentiation, and depth of invasion [14].
• The results of the clinical specimens showed that the Fra-1 gene was overexpressed in ESCC compared with normal esophageal epithelium in 53 of 61 cases (87%), Neogenin in 57 of 61 cases (93%), Id-1 in 57 of 61 cases (93%), and CDC25B in 48 of 61 cases (79%) [15].

Associations of CDC25B with chemical compounds

• However, phosphorylation of CDC25B does not stimulate its phosphatase activity, and mutation of serine 146 had no effect on its catalytic activity [8].
• In addition to these binding-site differences, we found that the binding of 14-3-3beta drove CDC25B to the cytoplasm and that mutation of serine-309 to alanine completely abolished the cytoplasmic localization of CDC25B [9].
• In contrast, p34cdc2 in U937-ASPI3K maintained in an active state by dephosphorylation on threonine 14 (Thr 14) and tyrosine 15 (Tyr 15), which was associated with constant nuclear CDC25A, CDC25B and CDC25C protein abundance before and after irradiation [16].
• In studying the subcellular localization of CDC25B, we found a functional NES at V52 to L65, the sequence of which is VTTLTQTMHDLAGL, where bold letters are leucine or hydrophobic amino acids frequently seen in an NES [17].
• Treatment with leptomycin B, a potent inhibitor of CRM1/exportin1, disrupted the cytoplasmic localization of both Flag-tagged CDC25B and NES-fused GFP [17].

Enzymatic interactions of CDC25B

• Our results demonstrate that Aurora-A phosphorylates CDC25B in vivo at the centrosome during mitosis [12].
• CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage [18].

Regulatory relationships of CDC25B

• Thus, interaction between 14-3-3 proteins and CDC25B is regulated in a manner that is different from that with CDC25C [19].
• Overexpression of cyclin-dependent kinase-activating CDC25B phosphatase in human gastric carcinomas [1].
• CDC25B phosphatases are essential regulators that control cyclin-dependent kinases activities at the entry into mitosis [8].

Other interactions of CDC25B

• We report that overexpression of CDC25B or CDC25C overrides an established CDT-induced G2 cell cycle arrest and leads the cells to accumulate in an abnormal mitotic stage with condensed chromatin and high CDK1 activity [20].
• Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition [12].
• This interaction is not increased upon phosphorylation of CDC25B by CHK1 and is not abolished by dephosphorylation [19].
• No obvious correlation was detected between the expression of CDC25B and p53 gene mutations [1].
• CDC25B is one of the three CDC25 phosphatase genes identified in human [21].

Analytical, diagnostic and therapeutic context of CDC25B

• Microinjection of antibodies against phosphorylated S353 results in a mitotic delay whilst overexpression of a S353 phosphomimetic mutant enhances the mitotic inducing effect of CDC25B [12].
• Western blot was employed to measure nuclear protein abundance of CDC25A, CDC25B, CDC25C, total p34cdc2, p34cdc2, (Thr 161) or p34cdc2 (Thr 14, Tyr 15) [16].
• Immunohistochemistry was carried out to localize and quantify CDC25B expression [2].
• CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting [2].
• Immunohistochemical stainings of securin and CDC25B showed a consistent expression pattern with that of cDNA microarray analysis [22].

References