Mitogens stimulate the rapid nuclear to cytosolic translocation of tristetraprolin, a potential zinc-finger transcription factor.
Mitogens stimulate the rapid nuclear to cytosolic translocation of tristetraprolin, a potential zinc-finger transcription factor.
复制标题
DOI：
10.1210/mend.10.2.8825554
复制
发表时间：
1996-02
影响因子：
--
通讯作者：
Gregory A. Taylor;Michael J. Thompson;W. Lai;P. Blackshear
中科院分区：
文献类型：
--
作者：
Gregory A. Taylor;Michael J. Thompson;W. Lai;P. Blackshear
Tristetraprolin(TTP)是一组潜在转录因子的原型，这些转录因子含有两个或更多不寻常的CCCH锌指。TTP由即刻早期反应基因ZFP-36编码，该基因在成纤维细胞中被胰岛素和其他生长因子快速诱导。间接证据表明，TTP可能是一种抑制转录因子。本研究通过胞核和胞浆组分的Western blotting评价了丝裂原对TTP亚细胞定位的影响。在组成性表达TTP的NIH/3T3小鼠成纤维细胞中，70%的蛋白质位于静止的、无血清的细胞的细胞核中。免疫活性TTP在血清刺激细胞的1分钟内开始增加；胞浆蛋白的增加基本上在血清刺激的5分钟内完成(占总数的81%)，并伴随着核TTP的相应减少。这种易位在血清刺激后TTP合成增加之前很久就完成了。在表达突变TTP的细胞中进行的类似实验，其中主要的丝裂原激活蛋白激酶位点(丝氨酸220)已突变为丙氨酸，显示血清刺激后正常的核到胞质易位，表明该位点的磷酸化不是发生这种易位所必需的。这些结果表明，TTP在有丝分裂原的响应下被迅速修饰，从而迅速从细胞核释放到胞浆中，或者是将TTP保留在细胞核中的蛋白质被修饰后释放到胞浆中。因此，TTP作为一种转录因子，可能是一种抑制因子，在细胞中可能部分地通过一种新的机制来调节，即快速、有丝分裂原刺激的转位出细胞核。
Tristetraprolin (TTP) is the prototype of a group of potential transcription factors that contain two or more unusual CCCH zinc fingers. TTP is encoded by the immediate-early response gene Zfp-36, which is rapidly induced in fibroblasts in response to insulin and other growth factors. Indirect evidence suggests that TTP might function as an inhibitory transcription factor. The present studies evaluated the effect of mitogens on the subcellular localization of TTP using Western blotting of cellular nuclear and cytosolic fractions. In NIH/3T3 mouse fibroblasts that constitutively express TTP, 70% of the protein was located in the nucleus of quiescent, serum-deprived cells. Immunoreactive TTP began to increase in the cytosolic compartment within 1 min of serum stimulation of the cells; this increase in cytosolic protein was essentially complete within 5 min of serum stimulation (81% of total) and was accompanied by a commensurate decrease in nuclear TTP. This translocation was complete well before the increase in TTP synthesis that occurred after serum stimulation. Similar experiments in cells expressing a mutant TTP, in which the major mitogen-activated protein kinase site (serine 220) had been mutated to alanine, revealed normal nuclear to cytosolic translocation after serum stimulation, indicating that phosphorylation of this site is not necessary for this translocation to occur. These results suggest that TTP is rapidly modified in response to mitogens so that it is rapidly released from the nucleus to the cytosol, or that proteins retaining TTP in the nucleus are modified to release it into the cytosol. Thus, TTP's proposed function as a transcription factor, possibly an inhibitory one, may be regulated in cells in part by a novel mechanism, i.e. that of rapid, mitogen-stimulated translocation out of the cellular nucleus.