Abstract
The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment.
Highlights
Reversible protein phosphorylation is an important molecular mechanism for the regulation of protein activity; this is true for many proteins that are essential for the regulation of important cellular events like intracellular signaling, cell cycle progression and proliferation, cellular differentiation and induction of apoptosis [1]
Because the cell division cycle 25 (CDC25) are essential for regulation of the cell cycle, their expression needs to be highly controlled
Dysregulation in the case of CDC25A, for example, accelerates the G1/S-phase transition [41], whereas an overexpression of CDC25B leads to premature mitotic entry [42]
Summary
Reversible protein phosphorylation is an important molecular mechanism for the regulation of protein activity; this is true for many proteins that are essential for the regulation of important cellular events like intracellular signaling, cell cycle progression and proliferation, cellular differentiation and induction of apoptosis [1]. The tyrosine phosphatases include a family of dual specificity phosphatases that hydrolyze both phosphotyrosines and serine/threonine phosphoesters; the cell division cycle 25 (CDC25) phosphatases are a subset among these dual specificity phosphatases [2] This family includes CDC25A, CDC25B and CDC25C [3]; these three enzymes are important regulators of several steps in the cell cycle and they possibly have a role in the development of a variety of human malignancies [2,4]. Cyclin-dependent kinases (CDKs) are important regulators of cell cycle progression, and CDK inhibition can be accomplished through inhibition of activating phosphatases [2]. By using cross-reactive CDC25 inhibitors it will be possible to target several steps in cell cycle regulation, including several cyclin-dependent kinases, through the use of a single therapeutic agent
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