Cop1 encodes a ubiquitin E3 ligase that has been well preserved during evolution in both plants and metazoans. In metazoans, the C/EBP family transcription factors are targets for degradation by Cop1, and this process is regulated by the Tribbles pseudokinase family. Over-expression of Tribbles homolog 1 (Trib1) induces acute myeloid leukemia (AML) via Cop1-dependent degradation of the C/EBPα p42 isoform. Here, we induced rapid growth arrest and granulocytic differentiation of Trib1-expressing AML cells using a Cop1 conditional knockout (KO), which is associated with a transient increase in the C/EBPα p42 isoform. The growth-suppressive effect of Cop1 KO was canceled by silencing of Cebpa and reinforced by exogenous expression of the p42 isoform. Moreover, Cop1 KO improved the survival of recipients transplanted with Trib1-expressing AML cells. We further identified a marked increase in Trib1 protein expression in Cop1 KO, indicating that Trib1 is self-degraded by the Cop1 degradosome. COP1 downregulation also inhibits the proliferation of human AML cells in a TRIB1-dependent manner. Taken together, our results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity, and a novel idea to develop new therapeutics.

Cop1编码泛素 E3 连接酶，该酶在植物和后生动物的进化过程中得到了很好的保存。在后生动物中，C/EBP 家族转录因子是 Cop1 降解的目标，并且该过程受到 Tribbles 假激酶家族的调节。 Tribbles 同源物 1 ( Trib1 ) 的过度表达通过 C/EBPα p42 同工型的 Cop1 依赖性降解诱导急性髓系白血病 (AML)。在这里，我们使用Cop1条件敲除 (KO) 诱导表达Trib1的 AML 细胞快速生长停滞和粒细胞分化，这与 C/EBPα p42 同种型的短暂增加有关。 Cop1 KO 的生长抑制作用被Cebpa的沉默所抵消，并被 p42 同种型的外源表达所增强。此外， Cop1 KO 提高了移植表达Trib1 的AML 细胞的受体的存活率。我们进一步发现Cop1 KO 中 Trib1 蛋白表达显着增加，表明 Trib1 被 Cop1 降解体自行降解。 COP1下调还以TRIB1依赖性方式抑制人 AML 细胞的增殖。总而言之，我们的结果为 Trib1/Cop1 机制在 C/EBPα p42 依赖性白血病活性中的作用提供了新的见解，并为开发新疗法提供了新思路。