Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line
Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line
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DOI：
10.1182/blood-2004-09-3701
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Möller, P
中科院分区：
文献类型：
--
作者：
Melzner, I;Bucur, AJ;Möller, P
原发性纵隔B细胞淋巴瘤（PMBL）是弥漫性大B细胞淋巴瘤的一个明确亚型。分子细胞遗传学显示9 p24的频繁增加。JAK 2定位于该区域，目前被认为是候选癌基因，因为表达谱显示高Janus激酶-2（JAK 2）转录水平，并且发现JAK 2在纵隔B细胞淋巴瘤中组成性磷酸化。我们在MedB-1纵隔中证实了这一点。B细胞系，携带三体9，JAK 2转录升高，产物。是.高度磷酸化。然而，JAK 2在蛋白质水平上没有过表达。此外，JAK 2蛋白的周转甚至会延迟。这一意外发现与该细胞中细胞因子信号传导抑制因子-1（SOCS-1）基因的双等位基因突变相一致，该突变消除了该蛋白的SOCS盒功能。MedB-1中野生型（wt）SOCS-1的异位表达导致生长停滞和磷酸化JAK 2及其下游伴侣磷酸化信号转导子和转录激活子-5（磷酸化STAT 5）的显著减少。最终，靶基因细胞周期蛋白D1在转染子中被抑制，而在MedB-1中沉默的RB 1被诱导。我们的结论是，在MedB-1，磷酸JAK 2的行动是持续的，由于有缺陷的SOCS-1。因此，SOCS-1有资格作为一种新的肿瘤抑制剂。值得注意的是，SOCS-1突变也存在于MedB-1的亲代肿瘤中，并在20个PMBLs中的9个中检测到。(c)2005年美国血液学会
Primary mediastinal B-cell lymphoma (PMBL) is a well-defined subtype of diffuse large B-cell lymphoma. Molecular cytogenetics revealed frequent gains of 9p24. JAK2, mapping in this region, is presently regarded as a candidate oncogene because expression profiling showed high Janus kinase-2 (JAK2) transcript levels and JAK2 was found to be constitutively phosphorylated in mediastinal B-cell lymphomas. We confirm that in the MedB-1 mediastinal. B-cell line, harboring a trisomy 9, JAK2 transcription is elevated and the product. is. highly phosphorylated. However, JAK2 is not overexpressed at the protein level. On top, JAK2 protein turnover is even delayed. This unexpected finding coincides with a biallelic mutation of the suppressor of cytokine signaling-1 (SOCS-1) gene in this cell, which abrogates SOCS box function of the protein. Ectopic expression of wild-type (wt) SOCS-1 in MedB-1 leads to growth arrest and dramatic reduction of phospho-JAK2 and its downstream partner phospho-signal transducer and activator of transcription-5 (phospho-STAT5). Ultimately, the target gene cyclin D1 is repressed in transfectants while RB1, which is silenced in MedB-1, is induced. We conclude that, in MedB-1, action of phospho-JAK2 is sustained due to defective SOCS-1. Hence, SOCS-1 qualifies as a novel tumor suppressor. Of note, SOCS-1 mutations are also present in the parental tumor of MedB-1 and were detected in 9 of 20 PMBLs. (c) 2005 by The American Society of Hematology