Antizyme targets cyclin D1 for degradation

A novel mechanism for cell growth repression

Ruchi M. Newman, Arian Mobascher, Ursula Mangold, Chieko Koike, Sri Diah, Marion Schmidt, Daniel Finley, Bruce R. Zetter

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)41504-41511
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number40
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

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Cyclin D1
Cell growth
Degradation
Growth
Ornithine Decarboxylase
Proteasome Endopeptidase Complex
Up-Regulation
Ubiquitination
Polyamines
Cell Cycle Proteins
Phosphorylation
Spermine
Ubiquitin
Metabolism
Adenosine Triphosphate
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Newman, R. M., Mobascher, A., Mangold, U., Koike, C., Diah, S., Schmidt, M., ... Zetter, B. R. (2004). Antizyme targets cyclin D1 for degradation: A novel mechanism for cell growth repression. Journal of Biological Chemistry, 279(40), 41504-41511. https://doi.org/10.1074/jbc.M407349200

Antizyme targets cyclin D1 for degradation : A novel mechanism for cell growth repression. / Newman, Ruchi M.; Mobascher, Arian; Mangold, Ursula; Koike, Chieko; Diah, Sri; Schmidt, Marion; Finley, Daniel; Zetter, Bruce R.

In: Journal of Biological Chemistry, Vol. 279, No. 40, 01.10.2004, p. 41504-41511.

Research output: Contribution to journalArticle

Newman, RM, Mobascher, A, Mangold, U, Koike, C, Diah, S, Schmidt, M, Finley, D & Zetter, BR 2004, 'Antizyme targets cyclin D1 for degradation: A novel mechanism for cell growth repression', Journal of Biological Chemistry, vol. 279, no. 40, pp. 41504-41511. https://doi.org/10.1074/jbc.M407349200
Newman RM, Mobascher A, Mangold U, Koike C, Diah S, Schmidt M et al. Antizyme targets cyclin D1 for degradation: A novel mechanism for cell growth repression. Journal of Biological Chemistry. 2004 Oct 1;279(40):41504-41511. https://doi.org/10.1074/jbc.M407349200
Newman, Ruchi M. ; Mobascher, Arian ; Mangold, Ursula ; Koike, Chieko ; Diah, Sri ; Schmidt, Marion ; Finley, Daniel ; Zetter, Bruce R. / Antizyme targets cyclin D1 for degradation : A novel mechanism for cell growth repression. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 40. pp. 41504-41511.
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