Burgess G S, Williamson E A, Cripe L D, Litz-Jackson S, Bhatt J A, Stanley K, Stewart M J, Kraft A S, Nakshatri H, Boswell H S
Walther Cancer Institute, and the Hematology/Oncology Division, the Departments of Medicine, and Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Blood. 1998 Oct 1;92(7):2450-60.
Activity of the c-jun N-terminal kinase (JNK) has been shown in hematopoietic cells transformed by p210 BCR-ABL. However, analysis has not been reported for hematopoietic cells on the consequences of this activity for c-jun promoter regulation within its distinctive proximal 8-base consensus CRE-like element, an element linked to JNK-mediated increase in c-jun transcription. In the present study, regulation of the proximal c-jun promoter was studied in murine myeloid cells transformed by p210 BCR-ABL. Promoter regulation in p210 BCR-ABL transformed cells was compared with regulation of the promoter in nontransformed interleukin-3 (IL-3)-dependent parental cells. The composition of nuclear AP-1 proteins contained within cells with p210 BCR-ABL, and their binding to the c-jun promoter proximal CRE-like element, was compared with the composition and binding of AP-1 proteins in IL-3-treated parental cells without p210 BCR-ABL. The present analysis found fivefold increased c-jun transcription occurring in p210 BCR-ABL transformed murine myeloid cells possessing a corresponding magnitude of increased kinase activity of JNK, compared with IL-3-stimulated parental cells. Augmented JNK activity was accompanied by increased nuclear abundance of c-jun and c-fos proteins that bound specifically to the proximal c-jun promoter CRE element. Also, representative human leukemic cell lines expressing p210 BCR-ABL and possessing abundant kinase activity of JNK, when compared with parental cells that were deficient in JNK activity, had increased c-jun and c-fos proteins. Finally, to show the relevance of these observations in model systems, we studied blast cells from patients with Philadelphia chromosome-positive acute leukemic transformation, and observed comparable activities of JNK catalysis and c-jun/AP-1 protein relative to the cell lines that possessed p210 BCR-ABL and JNK activity. These studies provide a basis for investigating the set of downstream genes which augmented c-jun/AP-1 activity enlists in the process of transformation by p210 BCR-ABL.
c-jun氨基末端激酶（JNK）的活性已在由p210 BCR-ABL转化的造血细胞中得到证实。然而，尚未有关于造血细胞中这种活性对其独特的近端8碱基共有CRE样元件内c-jun启动子调控的影响的分析报道，该元件与JNK介导的c-jun转录增加有关。在本研究中，我们研究了p210 BCR-ABL转化的小鼠髓系细胞中近端c-jun启动子的调控。将p210 BCR-ABL转化细胞中的启动子调控与未转化的白细胞介素-3（IL-3）依赖性亲代细胞中的启动子调控进行了比较。将含有p210 BCR-ABL的细胞中所含核AP-1蛋白的组成及其与c-jun启动子近端CRE样元件的结合，与无p210 BCR-ABL的IL-3处理的亲代细胞中AP-1蛋白的组成和结合进行了比较。本分析发现，与IL-3刺激的亲代细胞相比，在具有相应程度JNK激酶活性增加的p210 BCR-ABL转化的小鼠髓系细胞中，c-jun转录增加了五倍。JNK活性增强伴随着与近端c-jun启动子CRE元件特异性结合的c-jun和c-fos蛋白的核丰度增加。此外，与缺乏JNK活性的亲代细胞相比，表达p210 BCR-ABL并具有丰富JNK激酶活性的代表性人类白血病细胞系中，c-jun和c-fos蛋白增加。最后，为了在模型系统中展示这些观察结果的相关性，我们研究了费城染色体阳性急性白血病转化患者的原始细胞，并观察到与具有p210 BCR-ABL和JNK活性的细胞系相比，JNK催化和c-jun/AP-1蛋白的活性相当。这些研究为研究在p210 BCR-ABL转化过程中增强的c-jun/AP-1活性所募集的下游基因集提供了基础。
