title: Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of CDC25 overexpression and potential treatment strategies.
abstract: Alterations in the cell-cycle regulatory genes result in uncontrolled cell proliferation leading to several disease conditions. Cyclin-dependent kinases (CDK) and their regulatory subunit, cyclins, are essential proteins in cell-cycle progression. The activity of CDK is regulated by a series of phosphorylation and dephosphorylation at different amino acid residues. Cell Division Cycle-25 (CDC25) plays an important role in transitions between cell-cycle phases by dephosphorylating and activating CDKs. CDC25B and CDC25C play a major role in G2/M progression, whereas CDC25A assists in G1/S transition. Different isomers of CDC25 expressions are upregulated in various clinicopathological situations. Overexpression of CDC25A deregulates G1/S and G2/M events, including the G2 checkpoint. CDC25B has oncogenic properties. Binding to the 14-3-3 proteins regulates the activity and localization of CDC25B. CDC25C is predominantly a nuclear protein in mammalian cells. At the G2/M transition, mitotic activation of CDC25C protein occurs by its dissociation from 14-3-3 proteins along with its phosphorylation at multiple sites within its N-terminal domain. In this article, we critically reviewed the biology of the activation/deactivation of CDC25 by kinases/phosphatases to maintain the level of CDK-cyclin activities and thus the genomic stability, clinical implications due to dysregulation of CDC25, and potential role of CDC25 inhibitors in diseases.
authors.affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA.
authors.forename: Swastika
authors.initials: S
authors.lastname: Sur
authors.affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA. dkagr@creighton.edu.|Department of Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE, USA. dkagr@creighton.edu.|Creighton University School of Medicine, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA. dkagr@creighton.edu.
authors.forename: Devendra K
authors.identifier: http://orcid.org/0000-0003-0355-3025
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D042822:Genomic Instability; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008540:Meiosis; D010766:Phosphorylation; D020687:cdc25 Phosphatases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D007527:Isoenzymes; D018844:Cyclin-Dependent Kinases; D020687:cdc25 Phosphatases
keywords: CDC25 phosphatase; Cancer; Cell cycle; Intimal hyperplasia; Kinases