Gritli-Linde A, Nilsson J, Bohlooly-Y M, Heby O, Linde A
Department of Oral Biochemistry, Göteborg University, Göteborg, Sweden.
Dev Dyn. 2001 Mar;220(3):259-75. doi: 10.1002/1097-0177(20010301)220:3<259::AID-DVDY1100>3.0.CO;2-#.
The polyamines are important regulators of cell growth and differentiation. Cells acquire polyamines by energy-dependent transport and by synthesis where the highly regulated ornithine decarboxylase (ODC) catalyzes the first and rate-controlling step. Inactivation of ODC is mainly exerted by antizyme (AZ), a 20--25 kDa polyamine-induced protein that binds to ODC, inactivates it, and targets it for degradation by the 26S proteasome without ubiquitination. In the present study, we have performed a systematic analysis of the expression of ODC and AZ, at the mRNA and protein levels, during mouse development. The expression patterns for ODC and AZ were found to be developmentally regulated, suggesting important functions for the polyamines in early embryogenesis, axonogenesis, epithelial-mesenchymal interaction, and in apoptosis. In addition, AZ protein was found to translocate to the nucleus in a developmentally regulated manner. The nuclear localization is consistent with the fact that the amino acid sequence of AZ exhibits features that characterize nuclear proteins. Interestingly, we found that cultivation of mandibular components of the first branchial arch in the presence of a selective proteasome inhibitor caused ODC accumulation in the nucleus of a subset of cells, suggesting that the observed nuclear translocation of AZ is linked to proteasome-mediated ODC degradation in the nucleus. The presence of AZ in the nucleus may suggest that nuclear ODC activity is under tight control, and that polyamine production can be rapidly interrupted when those developmental events, which depend on access to nuclear polyamines, have been completed.
多胺是细胞生长和分化的重要调节因子。细胞通过能量依赖型转运和合成来获取多胺，其中高度受调控的鸟氨酸脱羧酶（ODC）催化第一步且是限速步骤。ODC的失活主要由抗酶（AZ）介导，AZ是一种20 - 25 kDa的多胺诱导蛋白，它与ODC结合，使其失活，并将其靶向26S蛋白酶体进行降解而无需泛素化。在本研究中，我们对小鼠发育过程中ODC和AZ在mRNA和蛋白质水平的表达进行了系统分析。发现ODC和AZ的表达模式受发育调控，这表明多胺在早期胚胎发生、轴突发生、上皮 - 间充质相互作用以及细胞凋亡中具有重要功能。此外，发现AZ蛋白以发育调控的方式转运至细胞核。这种核定位与AZ的氨基酸序列具有核蛋白特征这一事实相符。有趣的是，我们发现在选择性蛋白酶体抑制剂存在的情况下培养第一鳃弓的下颌成分会导致ODC在一部分细胞核中积累，这表明观察到的AZ核转运与蛋白酶体介导的细胞核中ODC降解有关。AZ在细胞核中的存在可能表明核ODC活性受到严格控制，并且当那些依赖于细胞核多胺的发育事件完成后，多胺的产生可以迅速中断。
