Department of Biochemistry and Molecular Biology, Medical School, United States.
Department of Biochemistry and Molecular Biology, Medical School, United States; Program of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
Cell Signal. 2014 Jul;26(7):1369-78. doi: 10.1016/j.cellsig.2014.03.006. Epub 2014 Mar 15.
Phorbol-12-myristate-13-acetate, also called PMA, is a small molecule that activates protein kinase C and functions to differentiate hematologic lineage cells. However, the mechanism of PMA-induced cellular differentiation is not fully understood. We found that PMA triggers global enhancement of protein ubiquitination in K562, a myelogenous leukemia cell line and one of the enhanced-ubiquitination targets is SnoN, an inhibitor of the Smad signaling pathway. Our data indicated that PMA stimulated the production of Activin A, a cytokine of the TGF-β family. Activin A then activated the phosphorylation of both Smad2 and Smad3. In consequence, SnoN is ubiquitinated by the APC(Cdh1) ubiquitin ligase with the help of phosphorylated Smad2. Furthermore, we found that SnoN proteolysis is important for the expression of CD61, a marker of megakaryocyte. These results indicate that protein ubiquitination promotes megakaryopoiesis via degrading SnoN, an inhibitor of CD61 expression, strengths the roles of ubiquitination in cellular differentiation.
十四烷酰佛波醇-13-乙酸酯，也称为 PMA，是一种能激活蛋白激酶 C 的小分子，可用于分化血液祖细胞。然而，PMA 诱导细胞分化的机制尚未完全阐明。我们发现 PMA 可触发 K562（一种髓系白血病细胞系）中蛋白质泛素化的全面增强，其中一个增强的泛素化靶标是 SnoN，它是 Smad 信号通路的抑制剂。我们的数据表明，PMA 刺激了激活素 A 的产生，激活素 A 是 TGF-β 家族的一种细胞因子。激活素 A 继而激活 Smad2 和 Smad3 的磷酸化。结果，在磷酸化 Smad2 的帮助下，SnoN 被 APC(Cdh1)泛素连接酶泛素化。此外，我们发现 SnoN 的蛋白水解对于 CD61（巨核细胞的标志物）的表达很重要。这些结果表明，蛋白质泛素化通过降解 SnoN 促进巨核细胞生成，SnoN 是 CD61 表达的抑制剂，从而增强了泛素化在细胞分化中的作用。
