Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter.
Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter.
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DOI：
10.1016/s0002-9440(10)64629-9
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发表时间：
2000-10
期刊：
影响因子：
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通讯作者：
Q. Zhang;P. N. Raghunath;E. Vonderheid;N. Odum;M. Wasik
中科院分区：
文献类型：
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作者：
Q. Zhang;P. N. Raghunath;E. Vonderheid;N. Odum;M. Wasik
SHP-1 是多种受体信号传导的重要负调节因子，包括白介素 2 (IL-2R) 和其他细胞因子受体。 SHP-1 通过使受体和受体相关激酶（例如 IL-2R 相关 Jak3 激酶）去磷酸化来发挥作用。我们发现，在大多数（七分之六）源自各种类型 T 细胞淋巴瘤的 T 细胞系和所有（八分之八）具有转化的大细胞形态的皮肤 T 细胞淋巴瘤组织中，SHP-1 蛋白未检测到或大大减少。所有测试的 T 细胞淋巴瘤系（八个中的八个）的 SHP-1 mRNA 表达量均减少或检测不到。然而，这些 T 细胞系的 SHP-1 基因编码、剪接连接和启动子区域不携带任何突变。重要的是，T 细胞系中的 SHP-1 DNA 启动子区域能够抵抗三种不同甲基化敏感限制酶的消化。通过用去甲基化剂 5-脱氧氮杂胞苷处理细胞，可以逆转这种耐药性。该治疗还导致 SHP-1 mRNA 的表达，以及较少出现的 SHP-1 蛋白的表达。 SHP-1 蛋白的表达与 Jak3 激酶的去磷酸化相关。这些结果表明，SHP-1 表达缺乏在恶性 T 细胞中很常见，这是由 SHP-1 基因启动子甲基化引起的。此外，他们表明 SHP-1 缺失可能通过允许 IL-2R 以及可能的其他受体复合物产生的信号持续存在而在 T 细胞淋巴瘤的发病机制中发挥作用。
SHP-1 is an important negative regulator of signaling by several receptors including receptors for interleukin-2 (IL-2R) and other cytokines. SHP-1 acts by dephosphorylating the receptors and receptor-associated kinases such as IL-2R-associated Jak3 kinase. We found that SHP-1 protein was not detectable or greatly diminished in most (six of seven) T cell lines derived from various types of T cell lymphomas and all (eight of eight) cutaneous T-cell lymphoma tissues with a transformed, large-cell morphology. All T-cell lymphoma lines tested (eight of eight) expressed diminished amounts or no detectable SHP-1 mRNA. These T cell lines did not, however, carry any mutations in the SHP-1 gene-coding, splice-junction, and promoter regions. Importantly, SHP-1 DNA promoter region in the T cell lines was resistant to digestion with three different methylation-sensitive restriction enzymes. This resistance was reversed by treatment of the cells with a demethylating agent, 5-deoxyazacytidine. The treatment resulted also in the expression of SHP-1 mRNA and, less frequently, SHP-1 protein. The expression of SHP-1 protein was associated with dephosphorylation of the Jak3 kinase. These results show that lack of SHP-1 expression is frequent in malignant T cells and results from methylation of the SHP-1 gene promoter. Furthermore, they indicate that SHP-1 loss may play a role in the pathogenesis of T cell lymphomas by permitting persistence of signals generated by IL-2R and, possibly, other receptor complexes.