B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos
B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos
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DOI：
10.1038/sj.onc.1203491
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发表时间：
2000-03-30
期刊：
影响因子：
8
通讯作者：
Taparowsky, EJ
中科院分区：
文献类型：
--
作者：
Echlin, DR;Tae, HJ;Taparowsky, EJ
B-ATF是一种核碱性亮氨酸拉链蛋白，属于AP-1/ATF转录因子超家族。Northern blot分析显示，人B-ATF基因在造血组织中表达量最高。体外和体内相互作用研究表明，B-ATF的亮氨酸拉链介导与Jun家族蛋白成员的二聚化。由部分B-ATF和酵母激活物GAL4的DNA结合域组成的嵌合蛋白不会刺激哺乳动物细胞中的报告基因表达，这表明B-ATF不包含传统的转录激活域。Jun/B-ATF二聚体显示出与Jun/Fos二聚体相似的DNA结合谱，其倾向于在CRE（环状amp反应元件）DNA位点上结合TRE （12- o -四碳多酚-13-乙酸酯反应元件）。B-ATF以剂量依赖的方式抑制含有TRE位点的报告基因的转录激活，可能是通过与Fos竞争Jun并形成转录惰性Jun/B-ATF异源二聚体，B-ATF在C3H10T1/2细胞中的稳定表达不会降低细胞活力，但与对照组相比，确实导致细胞生长速率降低，这种作用在H-Ras或v-Fos癌蛋白促进生长作用的存在下占主导地位。因为B-ATF的表达限制了这些转化剂形成焦点的效率。这些发现表明B-ATF是一种组织特异性转录因子，可能对AP-1起显性阴性作用。
B-ATF is a nuclear basic Leucine zipper protein that belongs to the AP-1/ATF superfamily of transcription factors. Northern blot analysis reveals that the human B-ATF gene is expressed most highly in hematopoietic tissues. Interaction studies in vitro and in vivo show that the leucine zipper of B-ATF mediates dimerization with members of the Jun family of proteins. Chimeric proteins consisting of portions of B-ATF and the DNA binding domain of the yeast activator GAL4 do not stimulate reporter gene expression in mammalian cells, indicating that B-ATF does not contain a conventional transcription activation domain. Jun/B-ATF dimers display similar DNA binding profiles as Jun/Fos dimers, with a bias toward binding TRE (12-O-tetradecanolyphorbol-13-acetate-response element) over CRE (cyclic AMP-response element) DNA sites. B-ATF inhibits transcriptional activation of a reporter gene containing TRE sites in a dose-dependent manner, presumably by competing with Fos for Jun and forming transcriptionally inert Jun/B-ATF heterodimers, Stable expression of B-ATF in C3H10T1/2 cells does not reduce cell viability, but does result in a reduced cellular growth rate when compared to controls, This effect is dominant in the presence of the growth promoting effects of the H-Ras or the v-Fos oncoproteins, since expression of B-ATF restricts the efficiency of focus formation by these transforming agents. These findings demonstrate that B-ATF is a tissue-specific transcription factor with the potential to function as a dominant-negative to AP-1.