Disruption of ZAS3 in mice alters NF-κB and AP-1 DNA binding and T-cell development
Disruption of ZAS3 in mice alters NF-κB and AP-1 DNA binding and T-cell development
复制标题
DOI：
10.3727/105221607783417574
复制
发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Wu, Lai-Chu
中科院分区：
文献类型：
--
作者：
Allen, Carl E.;Richards, John;Wu, Lai-Chu
大锌指蛋白，ZAS，调节参与细胞生长，发育和转移的多种基因的转录。它们还在TGF-β和TNF-α途径的信号转导中起作用。然而，内源性蛋白的代表性成员，ZAS 3，是迅速降解的初级淋巴细胞，这限制了其生理功能的测定在体外。因此，我们已经产生了具有ZAS 3靶向破坏的小鼠。基于寡核苷酸的微阵列分析揭示了基因表达的细微但一致的差异，其中许多与ZAS 3（+/+）和ZAS 3（-/-）胸腺之间的受体或信号转导活性相关。凝胶迁移率变动分析显示，在ZAS 3缺陷组织（包括胸腺）中，NF-κ B和AP-1蛋白的DNA结合活性发生改变。淋巴细胞分析表明ZAS 3在调节T细胞发育和活化中具有微妙但广泛的功能。在CD 3 + ZAS 3（-/-）胸腺细胞中，CD 4/CD 8比值降低，CD 69表达降低。在外周CD 4 + ZAS 3（-/-）淋巴细胞中，我们观察到记忆T细胞数量增加。
The large zinc finger proteins, ZAS, regulate the transcription of a variety of genes involved in cell growth, development, and metastasis. They also function in the signal transduction of the TGF-beta and TNF-alpha pathways. However, the endogenous protein of a representative member, ZAS3, is rapidly degraded in primary lymphocytes, which limits the determination of its physiological function in vitro. Therefore, we have generated mice with targeted disruption of ZAS3. Oligonucleotide-based microarray analyses revealed subtle but consistent differences in the expression of genes, many of which are associated with receptor or signal transduction activities between ZAS3(+/+) and ZAS3(-/-) thymi. Gel mobility shift assays showed altered DNA binding activities of NF-kappa B and AP-1 proteins in ZAS3-deficient tissues, including the thymus. Lymphocyte analysis suggested a subtle but broad function of ZAS3 in regulating T-cell development and activation. In CD3+ ZAS3(-/-) thymocytes, the CD4/CD8 ratio was decreased and CD69 expression was decreased. In peripheral CD4+ ZAS3(-/-) lymphocytes we observed an increased number of memory T cells.