STAT5 regulation of BCL10 parallels constitutive NFkappaB activation in lymphoid tumor cells.
STAT5 regulation of BCL10 parallels constitutive NFkappaB activation in lymphoid tumor cells.
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DOI：
10.1186/1476-4598-8-67
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发表时间：
2009-08-26
期刊：
影响因子：
37.3
通讯作者：
Kirken RA
中科院分区：
文献类型：
--
作者：
Nagy ZS;LeBaron MJ;Ross JA;Mitra A;Rui H;Kirken RA
信号转导子和转录激活子5 A和B（STAT 5）是淋巴系细胞中的关键存活因子。新的组织特异性STAT 5调节基因的鉴定将提高对抗由于异常STAT 5信号传导引起的疾病的能力。在本工作中，创建并验证了人STAT 5结合基因组元件的文库。在鉴定的几个STAT 5应答基因组调控元件中，一个位于人BCL 10基因的第一内含子内。染色质免疫沉淀反应证实了在各种人类淋巴肿瘤细胞系中STAT 5与该内含子片段的组成性体内结合。有趣的是，在不存在抑制组成型NFκB激活的细胞因子刺激的情况下，在Kit 225和YT细胞的细胞核中发现非磷酸化的STAT 5。在MT-2细胞中，通过曼尼希碱NC 1153抑制过度活跃的JAK 3/STAT 5通路，以剂量依赖性方式减少了STAT 5对BCL 10-SBR的组成性体内占据，降低了NFκB活性和BCL 10蛋白表达。此外，通过选择性反义寡核苷酸处理的STAT 5耗竭类似地导致BCL 10 mRNA和蛋白表达降低、细胞活力降低和NFκB活性受损，而不依赖于IL-2。这些结果表明，NFκB调节因子BCL 10是IL-2非依赖性STAT 5靶基因。这些发现提供了一种模型，其中未活化的STAT 5可以调节对淋巴细胞存活至关重要的途径，并且不依赖于酪氨酸磷酸化而破坏STAT 5功能的抑制剂在治疗某些白血病/淋巴瘤中可能是治疗有效的。
Signal Transducer and Activator of Transcription 5 A and B (STAT5) are key survival factors in cells of the lymphoid lineage. Identification of novel, tissue-specific STAT5 regulated genes would advance the ability to combat diseases due to aberrant STAT5 signaling. In the present work a library of human STAT5 bound genomic elements was created and validated. Of several STAT5 responsive genomic regulatory elements identified, one was located within the first intron of the human BCL10 gene. Chromatin immuno-precipitation reactions confirmed constitutive in vivo STAT5 binding to this intronic fragment in various human lymphoid tumor cell lines. Interestingly, non-phosphorylated STAT5 was found in the nuclei of Kit225 and YT cells in the absence of cytokine stimulation that paralleled constitutive NFκB activation. Inhibition of the hyperactive JAK3/STAT5 pathway in MT-2 cells via the Mannich-base, NC1153, diminished the constitutive in vivo occupancy of BCL10-SBR by STAT5, reduced NFκB activity and BCL10 protein expression in a dose dependent manner. Moreover, depletion of STAT5 via selective antisense oligonucleotide treatment similarly resulted in decreased BCL10 mRNA and protein expression, cellular viability and impaired NFκB activity independent of IL-2. These results suggest that the NFκB regulator BCL10 is an IL-2-independent STAT5 target gene. These findings proffer a model in which un-activated STAT5 can regulate pathways critical for lymphoid cell survival and inhibitors that disrupt STAT5 function independent of tyrosine phosphorylation may be therapeutically effective in treating certain leukemias/lymphomas.
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影响因子：
4.4
作者：
Behbod, F;Nagy, ZS;Kirken, RA
通讯作者：
Kirken, RA
DOI：
10.1073/pnas.75.8.3574
发表时间：
1978-01-01
影响因子：
11.1
作者：
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通讯作者：
CANDIDO, EPM
影响因子：
50.3
作者：
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通讯作者：
Sexl, Veronika
影响因子：
13.8
作者：
Orlando, V
通讯作者：
Orlando, V
影响因子：
4.8
作者：
Nelson, EA;Walker, SR;Frank, DA
通讯作者：
Frank, DA