Dual mode of degradation of Cdc25 A phosphatase
- 16 September 2002
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 21 (18), 4875-4884
- https://doi.org/10.1093/emboj/cdf491
Abstract
The Cdc25 dual‐specificity phosphatases control progression through the eukaryotic cell division cycle by activating cyclin‐dependent kinases. Cdc25 A regulates entry into S‐phase by dephosphorylating Cdk2, it cooperates with activated oncogenes in inducing transformation and is overexpressed in several human tumors. DNA damage or DNA replication blocks induce phosphorylation of Cdc25 A and its subsequent degradation via the ubiquitin–proteasome pathway. Here we have investigated the regulation of Cdc25 A in the cell cycle. We found that Cdc25 A degradation during mitotic exit and in early G1 is mediated by the anaphase‐promoting complex or cyclosome (APC/C)Cdh1 ligase, and that a KEN‐box motif in the N‐terminus of the protein is required for its targeted degradation. Interestingly, the KEN‐box mutated protein remains unstable in interphase and upon ionizing radiation exposure. Moreover, SCF (Skp1/Cullin/F‐box) inactivation using an interfering Cul1 mutant accumulates and stabilizes Cdc25 A. The presence of Cul1 and Skp1 in Cdc25 A immunocomplexes suggests a direct involvement of SCF in Cdc25 A degradation during interphase. We propose that a dual mechanism of regulated degradation allows for fine tuning of Cdc25 A abundance in response to cell environment.This publication has 51 references indexed in Scilit:
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