Mechanisms of polyamine-dependent control of ornithine decarboxylase and its antizyme

鸟氨酸脱羧酶及其抗酶的多胺依赖性控制机制

• 批准号: 5451277
• 负责人: Professor Dr. Jürgen Dohmen
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5451277?language=en
• 关键词: Mechanisms; polyamine; dependent; control; ornithine

Polyamines are essential organic cations with a variety of cellular functions. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in the biosynthesis of polyamines. ODC turnover is the paradigm of ubiquitin-independent proteolysis. Both in mammals and lower eukaryotes, ODC degradation is induced by high levels of polyamines, which thus constitutes a regulatory feedback control of polyamine biosynthesis. Work in mammals has revealed a mechanism wherein polyamines induce a ribosomal frameshifting during the decoding of an mRNA encoding ODC antizyme. This protein mediates degradation of ODC by the proteasome. We have discovered an ODC antizyme, termed Oaz1, in Saccharomyces cerevisiae that has long escaped detection due to its low but significant sequence similarity to mammalian antizymes. Oaz1 synthesis is controlled by polyamine-induced ribosomal frameshifting. Using the yeast model system we moreover discovered that Oaz1 levels are in addition controlled by ubiquitin-mediated proteolysis. Degradation of Oaz1 is inhibited by polyamines. In this project, we want to characterize the mechanisms that underlie polyamine-induced ribosomal frameshifting during decoding of OAZ1 mRNA and to characterize the principles of ubiquitinmediated proteolysis of Oaz1 and how this process is inhibited by polyamines. These studies are likely to be relevant for an understanding of the regulation of polyamine biosynthesis in higher organisms including humans as well.

多胺是具有多种细胞功能的必需有机阳离子。鸟氨酸脱羧酶（ODC）是多胺生物合成的限速酶。ODC周转是不依赖于泛素的蛋白质水解的范例。在哺乳动物和低等真核生物中，高水平的多胺诱导ODC降解，从而构成多胺生物合成的调节反馈控制。在哺乳动物中的工作已经揭示了一种机制，其中多胺诱导核糖体移码过程中的mRNA编码ODC抗酶的解码。该蛋白质介导蛋白酶体对ODC的降解。我们在酿酒酵母中发现了一种ODC抗酶，称为Oaz1，由于其与哺乳动物抗酶的低但显著的序列相似性而长期逃避检测。Oaz1合成受多胺诱导的核糖体移码控制。使用酵母模型系统，我们还发现，Oaz1的水平是另外控制的泛素介导的蛋白水解。Oaz1的降解被多胺抑制。在这个项目中，我们希望描述在OAZ1 mRNA解码过程中多胺诱导的核糖体移码的机制，并描述泛素介导的Oaz1蛋白水解的原理以及多胺如何抑制这一过程。这些研究可能是相关的了解多胺生物合成的调节高等生物体，包括人类以及。

项目成果

Co-translational Polyamine Sensing by Nascent ODC Antizyme

新生 ODC 抗酶的共翻译多胺传感

• DOI: 10.1007/978-4-431-55052-5_12
• 发表时间: 2014
• 作者: Palanimurugan;Kurian;Dohmen
• 通讯作者: Dohmen

Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins

• DOI: 10.1073/pnas.1216778110
• 发表时间: 2013-04-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Gowda, Naveen Kumar Chandappa;Kandasamy, Ganapathi;Andreasson, Claes
• 通讯作者: Andreasson, Claes

Ultrafiltration-based in vitro assay for determining polyamine binding to proteins

基于超滤的体外测定法测定多胺与蛋白质的结合

• DOI: 10.1038/protex.2012.005
• 发表时间: 2012
• 期刊: Protocol exchange
• 作者: Palanimurugan R;Dohmen R.J.
• 通讯作者: Dohmen R.J.

Ubiquitin, Ubiquitin-Like Proteins, and Proteasome-Mediated Degradation

泛素、泛素样蛋白和蛋白酶体介导的降解

• DOI: 10.1016/b978-0-12-394447-4.10069-0
• 发表时间: 2016
• 作者: Dohmen;Huibregtse;Scheffner
• 通讯作者: Scheffner