Functional analysis of Trib1/2 double knockout mice on hematopoiesis

Trib 1或Trib 2的过表达诱导急性髓性白血病（AML）。我们以前曾报道过，通过Trib 1与MEK 1的相互作用和C/EBPα的降解来增强MAP激酶途径是Trib 1的白血病活性所必需的。然而，Trib 1或Trib 2 KO（敲除）小鼠没有表现出严重的异常表型，并且不清楚Trib 1/2在正常组织中的功能。在本研究中，我们证明了Trib 1和Trib 2在E13.5胚胎和成年小鼠的许多组织中表现出不同的表达模式。此外，Trib 1 KO小鼠的骨髓显示分叶中性粒细胞、C/EBPα蛋白及其诱导粒细胞生成的靶基因增加。这些结果表明，Trib 1通过降解C/EBPα来调节粒细胞生成。另一方面，Trib 2 KO小鼠未显示异常分化，Trib 1/2双条件KO表明与Trib 1单KO相同水平的粒细胞生成。在正常骨髓细胞中，Trib 1的表达是Trib 2的5倍，表明Trib 1在调节粒细胞生成中起着重要作用

Overexpression of Trib1 or Trib2 induces acute myeloid leukemia (AML). We have previously reported that enhancement of MAP kinase pathway through interaction of Trib1 with MEK1 and degradation of C/EBPα is required for leukemic activity of Trib1. However Trib1 or Trib2 KO (knockout) mice did not indicate severely abnormal phenotype and it is no clear the Trib1/2 function in normal tissues. In this study, we demonstrated that Trib1 and Trib2 show different expression pattern in many tissues of E13.5 embryo and adult mice. In addition, bone marrow of Trib1 KO mice indicated increase of segmented neutrophils, C/EBPα protein and its target genes that induce granulopoiesis. These results suggest that Trib1 regulates granulopoiesis through degradation of C/EBPα. On the other hand, Trib2 KO mice did not show abnormal differentiation and Trib1/2 double conditional KO indicated the same level of granulopoiesis as Trib1 single KO. In normal bone marrow cells, expression of Trib1 is about 5 fold by compared with Trib2, indicating Trib1 dominantly plays a key role in regulation of granulopoiesis