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Regulation of all members of the antizyme family by antizyme inhibitor.
Biochem J. 2005 Jan 01; 385(Pt 1):21-8.BJ

Abstract

ODC (ornithine decarboxylase) is the rate-limiting enzyme in polyamine biosynthesis. Polyamines are essential for cellular growth and differentiation but enhanced ODC activity is associated with cell transformation. Post-translationally, ODC is negatively regulated through members of the antizyme family. Antizymes inhibit ODC activity, promote ODC degradation through the 26 S proteasome and regulate polyamine transport. Besides the ubiquitously expressed antizymes 1 and 2, there is the tissue-specific antizyme 3 and an yet uncharacterized antizyme 4. Antizyme 1 has been shown to be negatively regulated through the AZI (antizyme inhibitor) that binds antizyme 1 with higher affinity compared with ODC. In the present study, we show by yeast two- and three-hybrid protein-protein interaction studies that AZI interacts with all members of the antizyme family and is capable of disrupting the interaction between each antizyme and ODC. In a yeast-based ODC complementation assay, we show that human ODC is able to complement fully the function of the yeast homologue of ODC. Co-expression of antizymes resulted in ODC inhibition and cessation of yeast growth. The antizyme-induced growth inhibition could be reversed by addition of putrescine or by the co-expression of AZI. The protein interactions could be confirmed by immunoprecipitation of the human ODC-antizyme 2-AZI complexes. In summary, we conclude that human AZI is capable of acting as a general inhibitor for all members of the antizyme family and that the previously not yet characterized antizyme 4 is capable of binding ODC and inhibiting its enzymic activity similar to the other members of the antizyme family.

Authors+Show Affiliations

Center for Functional Genomics, Aventis Pharma GmbH, 82152 Martinsried, Germany. Ursula.Mangold@childrens.harvard.eduNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15355308

Citation

Mangold, Ursula, and Ekkehard Leberer. "Regulation of All Members of the Antizyme Family By Antizyme Inhibitor." The Biochemical Journal, vol. 385, no. Pt 1, 2005, pp. 21-8.
Mangold U, Leberer E. Regulation of all members of the antizyme family by antizyme inhibitor. Biochem J. 2005;385(Pt 1):21-8.
Mangold, U., & Leberer, E. (2005). Regulation of all members of the antizyme family by antizyme inhibitor. The Biochemical Journal, 385(Pt 1), 21-8.
Mangold U, Leberer E. Regulation of All Members of the Antizyme Family By Antizyme Inhibitor. Biochem J. 2005 Jan 1;385(Pt 1):21-8. PubMed PMID: 15355308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of all members of the antizyme family by antizyme inhibitor. AU - Mangold,Ursula, AU - Leberer,Ekkehard, PY - 2004/9/10/pubmed PY - 2005/6/29/medline PY - 2004/9/10/entrez SP - 21 EP - 8 JF - The Biochemical journal JO - Biochem. J. VL - 385 IS - Pt 1 N2 - ODC (ornithine decarboxylase) is the rate-limiting enzyme in polyamine biosynthesis. Polyamines are essential for cellular growth and differentiation but enhanced ODC activity is associated with cell transformation. Post-translationally, ODC is negatively regulated through members of the antizyme family. Antizymes inhibit ODC activity, promote ODC degradation through the 26 S proteasome and regulate polyamine transport. Besides the ubiquitously expressed antizymes 1 and 2, there is the tissue-specific antizyme 3 and an yet uncharacterized antizyme 4. Antizyme 1 has been shown to be negatively regulated through the AZI (antizyme inhibitor) that binds antizyme 1 with higher affinity compared with ODC. In the present study, we show by yeast two- and three-hybrid protein-protein interaction studies that AZI interacts with all members of the antizyme family and is capable of disrupting the interaction between each antizyme and ODC. In a yeast-based ODC complementation assay, we show that human ODC is able to complement fully the function of the yeast homologue of ODC. Co-expression of antizymes resulted in ODC inhibition and cessation of yeast growth. The antizyme-induced growth inhibition could be reversed by addition of putrescine or by the co-expression of AZI. The protein interactions could be confirmed by immunoprecipitation of the human ODC-antizyme 2-AZI complexes. In summary, we conclude that human AZI is capable of acting as a general inhibitor for all members of the antizyme family and that the previously not yet characterized antizyme 4 is capable of binding ODC and inhibiting its enzymic activity similar to the other members of the antizyme family. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/15355308/Regulation_of_all_members_of_the_antizyme_family_by_antizyme_inhibitor_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20040547 DB - PRIME DP - Unbound Medicine ER -