Kawamata Shin, Du Changchun, Li Kaijun, Lavau Catherine
SyStemix Inc. 3155 Porter Dr., Palo Alto, CA 94304, USA.
Oncogene. 2002 May 30;21(24):3855-63. doi: 10.1038/sj.onc.1205487.
To examine the effects of Notch signaling on hematopoiesis, we transplanted mice with progenitors transduced with a constitutively active form of Notch1 (Notch1IC) or the Notch1 target genes Hes. Notch1IC-transduced cells induce T cell tumors and cannot generate B lymphocytes in vivo. Hes-transplanted mice remained healthy but cells transduced with Hes1 or Hes5 were partially impaired in their ability to differentiate into B cells. Both Hes1 and Hes5 were upregulated in the BM of Notch1IC mice and their ability to interfere with the transcriptional activity of E2A in a reporter assay was comparable to that of Notch1IC. This suggests that the inhibition of B cell development in the Notch1IC-transduced cells could be mediated by the interference of HES1/HES5 proteins with E2A. Hes1-, Hes5- and Notch1IC-transduced bone marrow cells cultured ex vivo in a colony forming assay in the presence of cytokines that promote myeloid differentiation remained very immature, indicating that the myeloid potential of these bone marrow cells was altered. Thymocytes overexpressing Hes1, Hes5 or Notch1IC matured normally into CD4 and CD8 single positive cells in vivo. Altogether our data suggest that Notch1IC induces T cell tumors independently of Hes genes but that its interference with lymphoid B and myeloid maturation is partly mediated by Hes1 and Hes5. DOI:
为了研究Notch信号通路对造血作用的影响，我们用组成型激活形式的Notch1（Notch1IC）或Notch1靶基因Hes转导的祖细胞移植小鼠。Notch1IC转导的细胞会诱发T细胞肿瘤，且在体内无法生成B淋巴细胞。移植了Hes的小鼠保持健康，但用Hes1或Hes5转导的细胞在分化为B细胞的能力上部分受损。在Notch1IC小鼠的骨髓中，Hes1和Hes5均上调，并且在报告基因检测中，它们干扰E2A转录活性的能力与Notch1IC相当。这表明，Notch1IC转导细胞中B细胞发育的抑制可能是由HES1/HES5蛋白对E2A的干扰介导的。在促进髓系分化的细胞因子存在的情况下，在集落形成试验中离体培养的Hes1、Hes5和Notch1IC转导的骨髓细胞仍然非常不成熟，这表明这些骨髓细胞的髓系潜能发生了改变。过表达Hes1、Hes5或Notch1IC的胸腺细胞在体内正常成熟为CD4和CD8单阳性细胞。总之，我们的数据表明，Notch1IC独立于Hes基因诱导T细胞肿瘤，但其对淋巴B细胞和髓系成熟过程的干扰部分是由Hes1和Hes5介导的。数字对象标识符：
