Terme Jean-Michel, Lhermitte Ludovic, Asnafi Vahid, Jalinot Pierre
Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Institut Fédératif de Recherche 128 Biosciences Lyon Gerland, Lyon, France.
Blood. 2009 Jun 25;113(26):6695-8. doi: 10.1182/blood-2008-07-166835. Epub 2009 Apr 30.
T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor beta (TGF-beta), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-beta and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.
T细胞急性淋巴细胞白血病1（TAL1），也称为干细胞白血病（SCL），在造血细胞和内皮细胞的分化中起重要作用，并且在高比例的T细胞急性淋巴细胞白血病（T-ALL）中失调。在本报告中，我们表明TAL1的细胞内浓度受转化生长因子β（TGF-β）调节，TGF-β触发其多聚泛素化并被蛋白酶体降解。这种作用由AKT1介导，AKT1使TAL1的苏氨酸90磷酸化。免疫沉淀实验表明，该事件增加了TAL1与E3泛素连接酶CHIP的结合。TAL1的E47异二聚体伴侣阻碍这种结合。我们的观察结果表明，TGF-β和磷脂酰肌醇3-激酶/AKT途径的激活可能通过诱导这种重要癌基因的蛋白水解来逆转白血病细胞中TAL1的过表达。
