AML1 stimulates G1 to S progression via its transactivation domain
AML1 stimulates G1 to S progression via its transactivation domain
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DOI：
10.1038/sj.onc.1205447
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发表时间：
2002-05-09
期刊：
影响因子：
8
通讯作者：
Friedman, AD
中科院分区：
文献类型：
--
作者：
Bernardin, F;Friedman, AD
抑制aml1介导的转激活可有效减缓G1到S细胞周期的进展。在Ba/F3细胞中，用4-羟他莫昔芬激活外源性AML1 (RUNX1)-ER可阻止CBF癌蛋白CBF - smmhc介导的G1进展的抑制。我们在Ba/F3细胞中表达了三种AML1-ER与cbfβ - smmhc的变体。在这些细胞系中，CBFP-SMMHC的表达受锌响应型金属硫蛋白启动子的调控。删除72个AML1 c端残基（包括一个转抑制结构域）不会改变AML1- er的活性，而进一步删除98个残基（去除最有效的AML1反激活结构域（TAD））会阻止细胞周期抑制的恢复。值得注意的是，两种不刺激G1的变异加剧了cbfβ - smmhc介导的细胞周期阻滞，表明它们主要抑制AML1活性。此外，刺激G1的两种变体也诱导了5-15%的细胞凋亡，这与过度刺激G1的效果一致。这些观察结果表明，AML1通过其c端反激活结构域激活G1到S过渡的一个或多个关键基因的转录。急性白血病中AML的失活有望减缓增殖，除非存在加速G1的额外遗传改变。
Inhibition of AML1-mediated transactivation potently slows G1 to S cell cycle progression. In Ba/F3 cells, activation of exogenous AML1 (RUNX1)-ER with 4-hydroxytamoxifen prevents inhibition of G1 progression mediated by CBFbeta-SMMHC, a CBF oncoprotein. We expressed three AML1-ER variants with CBFbeta-SMMHC in Ba/F3 cells. In these lines, CBFP-SMMHC expression is regulated by the zinc-responsive metallothionein promoter. Deletion of 72 AML1 C-terminal residues, which includes a transrepression domain, did not alter the activity of AML1-ER, whereas further deletion of 98 residues, removing the most potent AML1 transactivation domain (TAD), prevented rescue of cell cycle inhibition. Notably, the two variants which did not stimulate G1 exacerbated CBFbeta-SMMHC-mediated cell cycle arrest, suggesting that they dominantly inhibit AML1 activities. In addition, the two variants which stimulated G I also induced apoptosis in 5-15% of the cells, an effect consistent with excessive G1 stimulation. These observations indicate that AML1 activates transcription of one or more genes critical for the G1 to S transition via its C-terminal transactivation domain. Inactivation of AML in acute leukemia is expected to slow proliferation unless additional genetic alterations co-exist which accelerate G1.