Antizyme targets cyclin D1 for degradation. A novel mechanism for cell growth repression.
Overproduction of the ornithine decarboxylase (ODC) regulatory protein ODC-antizyme has been shown to correlate with cell growth inhibition in a variety of different cell types. Although the exact mechanism of this growth inhibition is not known, it has been attributed to the effect of antizyme on polyamine metabolism. Antizyme binds directly to ODC, targeting ODC for ubiquitin-independent degradation by the 26 S proteasome. We now show that antizyme induction also leads to degradation of the cell cycle regulatory protein cyclin D1. We demonstrate that antizyme is capable of specific, noncovalent association with cyclin D1 and that this interaction accelerates cyclin D1 degradation in vitro in the presence of only antizyme, cyclin D1, purified 26 S proteasomes, and ATP. In vivo, antizyme up-regulation induced either by the polyamine spermine or by antizyme overexpression causes reduction of intracellular cyclin D1 levels. The antizyme-mediated pathway for cyclin D1 degradation is independent of the previously characterized phosphorylation- and ubiquitination-dependent pathway, because antizyme up-regulation induces the degradation of a cyclin D1 mutant (T286A) that abrogates its ubiquitination. We propose that antizyme-mediated degradation of cyclin D1 by the proteasome may provide an explanation for the repression of cell growth following antizyme up-regulation.
Newman
Ruchi M
RM
Program in Vascular Biology and Department of Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mobascher
Arian
A
Mangold
Ursula
U
Koike
Chieko
C
Diah
Sri
S
Schmidt
Marion
M
Finley
Daniel
D
Zetter
Bruce R
BR
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D025801:Ubiquitin; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D025801:Ubiquitin; C031017:ornithine decarboxylase antizyme; D019938:Cyclin D1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex