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TRIB2 regulates normal and stress-induced thymocyte proliferation

机译：TRIB2调节正常和应激诱导的胸腺细胞增殖

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TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2 ?/? developing thymocytes show increased proliferation, and Trib2 ?/? mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2 ?/? developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2 ?/? mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2 ?/? thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2 ?/? mice had reduced latency in vivo , which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function.
机译：TRIB2，一种被鉴定为致癌基因的丝氨酸/苏氨酸假激酶，在造血的T细胞区室中高水平表达。严格控制发育中的胸腺细胞的增殖，以防止T细胞发生白血病转化。在这里，我们研究了稳态和增生性应激条件（包括遗传毒性和致癌性应激）下小鼠造血功能的Trib2缺失。 Trib2 ？/？ 发育中的胸腺细胞显示增生，而Trib2 ？/？ 小鼠在稳定状态下的胸腺细胞性明显更高。在应激性造血过程中，Trib2 ？/？ 发育中的胸腺细胞经历了加速增殖并表现出对5-氟尿嘧啶（5-FU）诱导的细胞死亡的超敏性。尽管5-FU诱导的增殖应激后细胞死亡增加，但是Trib2 α/？ 小鼠由于发育中的胸腺细胞的细胞分裂动力学增强，治疗后的胸腺细胞恢复加快。 Trib2 ？/？中增殖的增加。 致癌应激下胸腺细胞恶化。在实验性小鼠T细胞急性淋巴细胞白血病（T-ALL）模型中，Trib2 ？/？ 小鼠体内的潜伏期缩短，这与MAP激酶（MAPK）激活受损有关。 Trib2的高和低表达水平分别与人类T-ALL的未成熟和成熟亚型相关，并与MAPK相关。因此，TRIB2成为胸腺细胞增殖的一种新型调节剂，对于对遗传毒性和致癌应激的胸腺生成反应很重要，并具有肿瘤抑制功能。

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