Dual mode of degradation of Cdc25 A phosphatase

Maddalena Donzelli, Massimo Squatrito, Dvora Ganoth, Avram Hershko, Michele Pagano, Giulio F. Draetta

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4875-4884
Number of pages10
JournalEMBO Journal
Volume21
Issue number18
DOIs
Publication statusPublished - Sep 16 2002

Keywords

  • A/cell cycle/cyclosome/SCF
  • APC/C/Cdc25

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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    Donzelli, M., Squatrito, M., Ganoth, D., Hershko, A., Pagano, M., & Draetta, G. F. (2002). Dual mode of degradation of Cdc25 A phosphatase. EMBO Journal, 21(18), 4875-4884. https://doi.org/10.1093/emboj/cdf491