Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin
Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin
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DOI：
10.1074/jbc.m504477200
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发表时间：
2005-10-21
影响因子：
4.8
通讯作者：
Park, M
中科院分区：
文献类型：
--
作者：
Long, JY;Zuo, DM;Park, M
上皮-间质转化（EMT）在胚胎发育和肿瘤发生中起重要作用. Smad相互作用蛋白1（SIP 1）通过募集辅阻遏物C末端结合蛋白（CtBP）抑制E钙粘蛋白的转录，从而诱导EMT. SIP 1的活性是如何调节的仍然不清楚。在这里，我们在体内和体外表明，SIP 1是共价修饰的sumoylation在两个保守的网站，赖氨酸（391）和赖氨酸（866）。多梳蛋白Pc 2，而不是皮亚斯（活化STAT的蛋白质抑制剂）家族蛋白，作为SIP 1的小泛素样修饰剂E3连接酶. SIP 1的SUMO化不影响其亚细胞定位，但调节其转录活性。与野生型相比，SIP 1类小泛素化无效突变体对E-钙粘蛋白转录表现出更强的抑制，但对两个转化生长因子-β-应答报告基因表现出类似的抑制，对维生素D3受体转录表现出相当的激活。SIP 1与Pc 2共表达可部分缓解SIP 1对E-钙粘蛋白的抑制作用。我们进一步表明SIP 1类小泛素化破坏了CtBP的募集。因此，SIP 1类小泛素化以启动子环境依赖的方式调节其转录活性，并可能代表调节肿瘤发生中EMT的重要干预靶点。
Epithelial- mesenchymal transition ( EMT) is important in embryonic development and tumorigenesis. Smad- interacting protein 1 ( SIP1) can induce EMT by repressing the transcription of E- cadherin through recruitment of the corepressor C- terminal- binding protein ( CtBP). How the activity of SIP1 is regulated still remains unclear. Here we show in vivo and in vitro that SIP1 is covalently modified by sumoylation at two conserved sites, Lys(391) and Lys(866). The polycomb protein Pc2, but not the PIAS ( protein inhibitor of activated STAT) family proteins, acts as a Small ubiquitin- like modifier E3 ligase for SIP1. Sumoylation of SIP1 does not affect its subcellular localization, but regulates its transcriptional activity. Compared with the wild- type, a SIP1 sumoylation null mutant shows more potent repression on E- cadherin transcription but similar repression on two transforming growth factor-beta- responsive reporter genes and comparable activation on vitamin D3 receptor transcription. Coexpression of SIP1 with Pc2 can partially relieve E- cadherin repression by SIP1. We further show that SIP1 sumoylation disrupts the recruitment of CtBP. Thus SIP1 sumoylation regulates its transcriptional activity in a promoter context- dependent manner and may represent an important intervention target to modulate EMT in tumorigenesis.