Krämer Oliver H, Müller Sylvia, Buchwald Marc, Reichardt Sigrid, Heinzel Thorsten
Institute of Biochemistry and Biophysics, University of Jena, Philosophenweg 12, D-07743 Jena, Germany.
FASEB J. 2008 May;22(5):1369-79. doi: 10.1096/fj.06-8050com. Epub 2007 Dec 11.
The chromosomal translocation products AML1-ETO and PML-RARalpha contribute to the pathogenesis of leukemias. Here, we demonstrate that both AML1-ETO and PML-RARalpha are degraded by the ubiquitin-proteasome system and that their turnover critically depends on the E2-conjugase UbcH8 and the E3-ligase SIAH-1. Contrary to its role in HDAC2 degradation, the E3-ligase RLIM does not target AML1-ETO and PML-RARalpha for ubiquitin-dependent elimination. RLIM rather is a substrate of SIAH-1, which indicates that these E3-ligases operate in a hierarchical order. Remarkably, proteasomal degradation of leukemia fusion proteins, in addition to the block of histone deacetylase (HDAC) enzymatic activity is a consequence of HDAC-inhibitor treatment. The former requires the induction of UbcH8 expression and each of these processes might be beneficial for leukemia treatment. Our observations shed light on the mechanism determining the interplay between E2-conjugases, E3-ligases, and their substrates and suggest a strategy for utilizing the ubiquitylation machinery in a therapeutic setting.
染色体易位产物AML1-ETO和PML-RARα在白血病发病机制中起作用。在此，我们证明AML1-ETO和PML-RARα均被泛素-蛋白酶体系统降解，且它们的周转关键依赖于E2连接酶UbcH8和E3连接酶SIAH-1。与它在HDAC2降解中的作用相反，E3连接酶RLIM并不将AML1-ETO和PML-RARα作为泛素依赖性消除的靶点。相反，RLIM是SIAH-1的底物，这表明这些E3连接酶按等级顺序发挥作用。值得注意的是，白血病融合蛋白的蛋白酶体降解，除了组蛋白脱乙酰酶（HDAC）酶活性的阻断外，是HDAC抑制剂治疗的结果。前者需要诱导UbcH8表达，且这些过程中的每一个可能都对白血病治疗有益。我们的观察结果揭示了决定E2连接酶、E3连接酶及其底物之间相互作用的机制，并提出了在治疗环境中利用泛素化机制的策略。
