Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL),FEBS Letters

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Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL)
FEBS Letters ( IF 3.0 ) Pub Date : 2021-08-28 , DOI: 10.1002/1873-3468.14186
Xu Hannah Zhang ₁ , Chih-Hong Chen ₁ , Hongzhi Li ₁ , Jack Hsiang ₁ , Xiwei Wu ₁ , Weidong Hu ₁ , David Horne ₁ , Sangkil Nam ₁ , Jack Shively ₁ , Steven T Rosen ₁

Affiliation

We describe here for the first time a lipid-binding-domain (LBD) in p38γ mitogen-activated protein kinase (MAPK) involved in the response of T cells to a newly identified inhibitor, CSH71. We describe how CSH71, which binds to both the LBD and the ATP-binding pocket of p38γ, is selectively cytotoxic to CTCL Hut78 cells but spares normal healthy peripheral blood mononuclear (PBMC) cells, and propose possible molecular mechanisms for its action. p38γ is a key player in CTCL development, and we expect that the ability to regulate its expression by specifically targeting the lipid-binding domain will have important clinical relevance. Our findings characterize novel mechanisms of gene regulation in T lymphoma cells and validate the use of computational screening techniques to identify inhibitors for therapeutic development.

中文翻译：

靶向 MAP 激酶 p38γ 的非 ATP 结合口袋介导皮肤 T 细胞淋巴瘤 (CTCL) 细胞毒性的新机制

我们在这里首次描述了参与 T 细胞对新发现的抑制剂 CSH71 的反应的 p38γ 丝裂原活化蛋白激酶 (MAPK) 中的脂质结合结构域 (LBD)。我们描述了与 LBD 和 p38γ 的 ATP 结合口袋结合的 CSH71 如何对 CTCL Hut78 细胞具有选择性细胞毒性，但不会影响正常健康的外周血单核 (PBMC) 细胞，并提出了其作用的可能分子机制。p38γ 是 CTCL 发展的关键参与者，我们预计通过特异性靶向脂质结合域来调节其表达的能力将具有重要的临床意义。我们的研究结果表征了 T 淋巴瘤细胞中基因调控的新机制，并验证了使用计算筛选技术来识别用于治疗开发的抑制剂。

更新日期：2021-10-25

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