Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase
Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase
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DOI：
10.1182/blood.v92.7.2450.2450_2450_2460
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发表时间：
1998-10-01
期刊：
影响因子：
20.3
通讯作者：
Boswell, HS
中科院分区：
文献类型：
--
作者：
Burgess, GS;Williamson, EA;Boswell, HS
在p210 BCR-ABL转化的造血细胞中，c-jun N-末端激酶（JNK）具有活性，但在造血细胞中，JNK活性对c-jun启动子调控的影响尚未见报道。本研究在p210 BCR-ABL转化的小鼠髓系细胞中研究了c-jun近端启动子的调控，并将p210 BCR-ABL转化细胞中的启动子调控与非转化的白细胞介素-3（IL-1）依赖性亲本细胞中的启动子调控进行了比较。p210 BCR-ABL细胞内所含的核AP-1蛋白的组成及其与c-jun启动子近端的CRE样元件的结合，与IL-3处理的无p210 BCR-ABL的亲本细胞中AP-1蛋白的组成和结合进行了比较。与IL-3刺激的亲本细胞相比，ABL转化的鼠骨髓细胞具有相应程度的JNK激酶活性增加，JNK活性的增强伴随着c-jun和c-fos蛋白的核丰度的增加，这些蛋白特异性地结合到近端的c-fos。jun启动子CRE元件。此外，与缺乏JNK活性的亲本细胞相比，表达p210 BCR-ABL并具有丰富的JNK激酶活性的代表性人白血病细胞系具有增加的c-jun和c-fos蛋白。最后，为了显示这些观察结果在模型系统中的相关性，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JNK催化和c-jun/AP-1蛋白相对于具有p210 BCR-ABL和JNK活性的细胞系的可比活性。这些研究为研究在p210 BCR-ABL转化过程中增加c-jun/AP-1活性的下游基因组提供了基础。（C）1998，美国血液学学会。
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-l)-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) 1998 by The American Society of Hematology.