Physiological Functions of Cdc25

Cdc25 was identified initially in the fission yeast Schizosac-charomyces pombe [4]. In this organism, cells with conditional mutations in the Cdc25 protein are unable to enter mitosis at the restrictive temperature and thus continue to grow into highly elongated cells. In further studies, it was shown that the timing of mitosis is highly dependent on the intracellular concentration of Cdc25. Cells with a reduced amount of active Cdc25 undergo mitosis at abnormally late times. Conversely, cells with elevated levels of Cdc25 enter mitosis with accelerated kinetics.

Biochemical studies in the early 1990s established that Cdc25 contains an intrinsic phosphatase activity [5-7]. Cdc25 is capable of dephosphorylating both phosphotyro-sine and phosphothreonine and is thus a member of the dual-specificity phosphatase family [8]. Like other dual-specificity phosphatases, Cdc25 absolutely requires a key cysteine residue for catalysis. Accordingly, Cdc25 requires a

Figure 1 Posttranslational regulation of MPF. Cdc2 is positively regulated by phosphorylation on Thr-161 by the Cdk-activating kinase (CAK). Cdc2 is negatively regulated by phosphorylation on Thr-14 and Tyr-15.

Interphase Myt1 Weet Mitosis

(inactive) (active)

Figure 1 Posttranslational regulation of MPF. Cdc2 is positively regulated by phosphorylation on Thr-161 by the Cdk-activating kinase (CAK). Cdc2 is negatively regulated by phosphorylation on Thr-14 and Tyr-15.

reducing agent (e.g., dithiothreitol) for activity and is highly sensitive to alkylating agents such as N-ethylmaleimide. Cdc25 is also potently inhibited by phosphomimetic compounds such as sodium orthovanadate.

In vertebrates, the Cdc25 family contains three distinct members: Cdc25A, Cdc25B, and Cdc25C [9-11]. The existence of these distinct enzymes can be rationalized by the fact that the Cdk family is more elaborate in vertebrates than in yeast. For example, a complex consisting of Cdk2 and cyclin E has a role in the G1/S transition. Cdc25A can remove inhibitory phosphate groups from Cdk2 [11]. Cdc25B and Cdc25C have both been implicated in mitotic regulation. Cdc25C can dephosphorylate the Cdc2-cyclin B complex effectively. Evidence has been presented that Cdc25B acts at some point upstream of Cdc25C in the mitotic control circuit [11]. Intriguingly, knockout mice that do not express Cdc25C are viable, suggesting that there is a functional redundancy among Cdc25 family members [12].

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