Stable Form of JAB1 Enhances Proliferation and Maintenance of Hematopoietic Progenitors
Stable Form of JAB1 Enhances Proliferation and Maintenance of Hematopoietic Progenitors
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DOI：
10.1074/jbc.m804539200
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发表时间：
2008-10-24
影响因子：
4.8
通讯作者：
Kato, Jun-ya
中科院分区：
文献类型：
--
作者：
Mori, Masaaki;Yoneda-Kato, Noriko;Kato, Jun-ya
在多种人类癌症中观察到JAB 1的过表达，但JAB 1如何参与肿瘤发展仍有待研究。在这里，我们分析了修饰Jab 1表达的小鼠。小鼠异位表达一种更稳定的形式的JAB 1蛋白的组成型启动子的控制下被救出的胚胎致死性引起的Jab 1（-/-）等位基因和基因剂量依赖性的方式发展骨髓增生性疾病。来自Jab 1转基因小鼠骨髓的造血细胞具有显著更大的干细胞群体，并且表现出更高的可移植增殖潜能。相比之下，Jab 1（-/-）小鼠，其表达的JAB 1蛋白与野生型同窝小鼠相似，为70%，表现出造血功能低下。肿瘤抑制基因p16（INK 4a）的表达与JAB 1的表达呈负相关，新发现的JAB 1相互作用蛋白SMYD 3与JAB 1共同抑制p16的转录。因此，JAB 1的表达和功能对于造血祖细胞的增殖和维持至关重要。
Overexpression of JAB1 is observed in a variety of human cancers, but how JAB1 is involved in tumor development remained to be investigated. Here we analyzed mice with modified Jab1 expression. Mice ectopically expressing a more stable form of JAB1 protein under the control of a constitutive promoter were rescued from the embryonic lethality caused by the Jab1(-/-) allele and developed a myeloproliferative disorder in a gene dosage-dependent manner. Hematopoietic cells from the bone marrow of Jab1 transgenic mice had a significantly larger stem cell population and exhibited higher and transplantable proliferative potential. In contrast, Jab1(-/-) mice, which express similar to 70% as much JAB1 protein as their wild-type littermates, showed inefficient hematopoiesis. Expression of the tumor suppressor p16(INK4a) was inversely correlated with that of JAB1, and the oncoprotein SMYD3, a newly identified JAB1 interactor, suppressed transcription of p16 in cooperation with JAB1. Thus, the expression and function of JAB1 are critical for the proliferation and maintenance of hematopoietic progenitors.