MAGE proteins regulate KRAB zinc finger transcription factors and KAP1 E3 ligase activity.
MAGE proteins regulate KRAB zinc finger transcription factors and KAP1 E3 ligase activity.
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MAGE 蛋白调节 KRAB 锌指转录因子和 KAP1 E3 连接酶活性。
DOI：
10.1016/j.abb.2014.07.026
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发表时间：
2014
影响因子：
3.9
通讯作者：
Longley,BJack
中科院分区：
文献类型：
--
作者：
Xiao,TonyZ;Suh,Yewseok;Longley,BJack
黑色素瘤抗原编码（melanomaantigenencoding， MAGE）基因的表达，尤其是MAGE- a3，与恶性黑色素瘤和其他恶性肿瘤的侵袭性临床病程、获得化疗耐药性和不良临床结果相关。MAGE蛋白与KAP1结合，KAP1是一种基因抑制因子和泛素E3连接酶，也结合含有锌指转录因子（KZNFs）的KRAB结构域，MAGE的表达可能影响KZNF介导的基因调控。为了研究这些影响的机制，我们验证了KRAB结构域组成差异影响KZNF多泛素化的假设，并确定MAGE表达是否会增加、减少或不影响KZNF介导的基因抑制。利用对KRAB结构域融合蛋白抑制反应的整合报告基因，我们发现MAGE-A3缓解了KZNF介导的抑制，并诱导与A+B盒KRAB结构域表达相关的KZNF多泛素化和降解。相比之下，MAGE-A3增强了KAP1介导的表达A或A+b盒KRAB结构域的KZNFs的抑制，但未引起多泛素化或降解的增加。MAGE-A3对含有Scan box motif的KRAB结构域的KZNFs无显著影响。这些数据支持我们的假设，表明MAGE-A3对基因抑制的影响取决于所涉及的KZNF KRAB结构域的类型。
Expression ofMelanomaAntiGenEncoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.