Mammalian Cdh1/Fzr mediates its own degradation.
The Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase mediates degradation of cell cycle proteins during mitosis and G1. Cdc20/Fzy and Cdh1/Fzr are substrate-specific APC/C activators. The level of mammalian Cdh1 is high in mitosis, but it is inactive and does not bind the APC/C. We show that when Cdh1 is active in G1 and G0, its levels are considerably lower and almost all of it is APC/C associated. We demonstrate that Cdh1 is subject to APC/C-specific degradation in G1 and G0, and that this degradation depends upon two RXXL-type destruction boxes. We further demonstrate that addition of Cdh1 to Xenopus interphase extracts, which have an inactive APC/C, activates it to degrade Cdh1. These observations indicate that Cdh1 mediates its own degradation by activating the APC/C to degrade itself. Elevated levels of Cdh1 are deleterious for cell cycle progression in various organisms. This auto-regulation of Cdh1 could thus play a role in ensuring that the level of Cdh1 is reduced during G1 and G0, allowing it to be switched off at the correct time.
Listovsky
Tamar
T
Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
Oren
Yifat S
YS
Yudkovsky
Yana
Y
Mahbubani
Hiro M
HM
Weiss
Aryeh M
AM
Lebendiker
Mario
M
Brandeis
Michael
M
D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015739:Nocodazole / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D015739:Nocodazole