Development：周建峰研究组首次揭示GPx4抑制Wnt通路，并在胚胎发育早期及癌症中发挥重要作用

2017-04-29 佚名中国海洋大学医药学院

经典Wnt信号通路是一条在物种间非常保守的信号通路。它调节着诸多生物学过程，在细胞形态与功能的分化与维持、胚胎发育、器官形成等过程中均发挥重要作用。该通路的异常会导致包括多种癌症在内的诸多疾病的发生。硒蛋白是动物体内相对稀少(目前发现人有25个硒蛋白)的一类翻译依赖硒的蛋白。硒主要通过形成特定的氨基酸即硒代半胱氨酸(Selenocysteine， Sec) 参与蛋白质的翻译。编码Sec的UGA 密

经典Wnt信号通路是一条在物种间非常保守的信号通路。它调节着诸多生物学过程，在细胞形态与功能的分化与维持、胚胎发育、器官形成等过程中均发挥重要作用。该通路的异常会导致包括多种癌症在内的诸多疾病的发生。硒蛋白是动物体内相对稀少(目前发现人有25个硒蛋白)的一类翻译依赖硒的蛋白。硒主要通过形成特定的氨基酸即硒代半胱氨酸(Selenocysteine， Sec) 参与蛋白质的翻译。编码Sec的UGA 密码子具有双重作用：细胞内硒充足时，UGA 密码子编码成Sec，硒蛋白可以被完整翻译；细胞内硒缺乏时，硒蛋白翻译则会在UGA 处终止，成为不完整且没有功能的蛋白。由于Sec作为催化活性中心具有较低还原电势，目前几乎所有已知硒蛋白都是氧化还原酶，其在细胞质中利用谷胱甘肽（Glutathione）作为底物清楚氧自由基从而保护细胞免受氧化损伤。最新研究发现在胚胎中，硒蛋白谷胱甘肽过氧化物酶4（Glutathione peroxidase 4， GPx4）在生物体发育早期的表达呈现动态变化，在几个特定时期该蛋白定位在细胞核，但其详细及更多的功能尚不清楚。在一项对肝癌的研究中发现，人及诱导性斑马鱼肝癌中共同存在12个表达下调基因，GPx4属于其中之一，但其原因及功能尚未知。

周建峰课题组在开展与癌症密切相关的Wnt/β-catenin 信号通路的全新调控因子大规模筛选时，首次发现GPx4能参与Wnt信号通路。通过模式动物斑马鱼发现GPx4调控早期胚胎背腹体轴发育；结合体外哺乳动物细胞系表明，GPx4均能负调Wnt/β-catenin 信号通路活性；遗传互作实验表明GPx4作用于核内转录因子Tcf/Lef水平，且不依赖于Sec位点的活性；深入揭示其作用机制，通过蛋白和染色质免疫共沉淀表明GPx4与Tcf/Lef相结合，进一步阻碍Tcf/Lef与靶基因的启动子结合进而发挥抑制Wnt通路活性的作用。该研究首次揭示硒蛋白GPx4具有负向调控Wnt/β-catenin 信号通路的作用，为更全面理解Wnt/β-catenin 信号通路调控网络提供有价值的参考，为拓展硒蛋白在生物体生命活动中的功能提供重要的依据。鉴于Wnt/β-catenin 信号通路与癌症的密切关系，本研究还将进一步拓宽对硒蛋白及含硒化合物在癌症等疾病中的作用认识，为开展此类药物设计及药物靶标研究提供思路和依据。

该研究得到了科技部国家重大科学研究计划、国家自然科学基金、中央高校基本科研业务费和青岛海洋科学与技术国家实验室的资助。研究成果2017年3月在线发表在Development杂志，论文第一作者为荣小至博士，通讯作者为周建峰教授。

原始出处：

Xiaozhi Rong， Yumei Zhou， Yunzhang Liu， et al.Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos.Development 2017 ： doi： 10.1242/dev.144261

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2017-09-21 jiyangfei

#重要作用#

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2017-07-19 fzwish20000

#Dev#

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2017-05-01 ailian1202

#胚胎#

52 0
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channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18725, encryptionId=c4da18e2588, topicName=WNT)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=eb3518632538, createdName=zhwj, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192391, encodeId=50af192391d8, content=新的研究通路, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Mon May 01 07:14:08 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192026, encodeId=31ac1920268a, content=学习了，谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Apr 30 06:51:08 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191962, encodeId=752f19196245, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 30 00:08:03 CST 2017, time=2017-04-30, status=1, ipAttribution=), 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2017-05-01 neurowu

#发育#

59 0
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channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18725, encryptionId=c4da18e2588, topicName=WNT)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=eb3518632538, createdName=zhwj, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192391, encodeId=50af192391d8, content=新的研究通路, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Mon May 01 07:14:08 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192026, encodeId=31ac1920268a, content=学习了，谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Apr 30 06:51:08 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191962, encodeId=752f19196245, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 30 00:08:03 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191947, encodeId=31fc19194ec4, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=95, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/AiafG5m7kibldQyTnpaQicxg1rnBqFdIGgQBJJs4lR8ibmh91PibzgL7R7pl2HSBjgFeeKRV0mMCvDh49LrgJPCYYvA/132, createdBy=abc91707732, createdName=qjzhai1623, createdTime=Sun Apr 30 00:04:05 CST 2017, time=2017-04-30, status=1, ipAttribution=)]
2017-05-01 huangshifeng

#GPx4#

76 0
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encryptionId=88713e938c1, topicName=发育)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f4c124, createdName=neurowu, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1423886, encodeId=27da1423886bf, content=<a href='/topic/show?id=b7d1822e38' target=_blank style='color:#2F92EE;'>#GPx4#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8227, encryptionId=b7d1822e38, topicName=GPx4)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=25333863783, createdName=huangshifeng, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598578, encodeId=a29615985e87c, content=<a href='/topic/show?id=c4da18e2588' target=_blank style='color:#2F92EE;'>#WNT#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18725, encryptionId=c4da18e2588, topicName=WNT)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=eb3518632538, createdName=zhwj, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192391, encodeId=50af192391d8, content=新的研究通路, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Mon May 01 07:14:08 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192026, encodeId=31ac1920268a, content=学习了，谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Apr 30 06:51:08 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191962, encodeId=752f19196245, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 30 00:08:03 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191947, encodeId=31fc19194ec4, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=95, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/AiafG5m7kibldQyTnpaQicxg1rnBqFdIGgQBJJs4lR8ibmh91PibzgL7R7pl2HSBjgFeeKRV0mMCvDh49LrgJPCYYvA/132, createdBy=abc91707732, createdName=qjzhai1623, createdTime=Sun Apr 30 00:04:05 CST 2017, time=2017-04-30, status=1, ipAttribution=)]
2017-05-01 zhwj

#WNT#

44 0
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createdName=fzwish20000, createdTime=Wed Jul 19 14:31:00 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1315340, encodeId=c73d13153401e, content=<a href='/topic/show?id=6fcc83e0554' target=_blank style='color:#2F92EE;'>#胚胎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83705, encryptionId=6fcc83e0554, topicName=胚胎)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6393434, createdName=ailian1202, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1347164, encodeId=776a134e16471, content=<a href='/topic/show?id=88713e938c1' target=_blank style='color:#2F92EE;'>#发育#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37938, 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GetPortalCommentsPageByObjectIdResponse(id=191947, encodeId=31fc19194ec4, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=95, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/AiafG5m7kibldQyTnpaQicxg1rnBqFdIGgQBJJs4lR8ibmh91PibzgL7R7pl2HSBjgFeeKRV0mMCvDh49LrgJPCYYvA/132, createdBy=abc91707732, createdName=qjzhai1623, createdTime=Sun Apr 30 00:04:05 CST 2017, time=2017-04-30, status=1, ipAttribution=)]
2017-05-01 doctorJiangchao

新的研究通路

94 0
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createdName=fzwish20000, createdTime=Wed Jul 19 14:31:00 CST 2017, time=2017-07-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1315340, encodeId=c73d13153401e, content=<a href='/topic/show?id=6fcc83e0554' target=_blank style='color:#2F92EE;'>#胚胎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83705, encryptionId=6fcc83e0554, topicName=胚胎)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6393434, createdName=ailian1202, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1347164, encodeId=776a134e16471, content=<a href='/topic/show?id=88713e938c1' target=_blank style='color:#2F92EE;'>#发育#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37938, 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2017-04-30 龙胆草

学习了，谢谢分享

84 0
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2017-04-30 飛歌

学习了很有用

74 0
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encryptionId=88713e938c1, topicName=发育)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f4c124, createdName=neurowu, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1423886, encodeId=27da1423886bf, content=<a href='/topic/show?id=b7d1822e38' target=_blank style='color:#2F92EE;'>#GPx4#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8227, encryptionId=b7d1822e38, topicName=GPx4)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=25333863783, createdName=huangshifeng, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1598578, encodeId=a29615985e87c, content=<a href='/topic/show?id=c4da18e2588' target=_blank style='color:#2F92EE;'>#WNT#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18725, encryptionId=c4da18e2588, topicName=WNT)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=eb3518632538, createdName=zhwj, createdTime=Mon May 01 10:31:00 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192391, encodeId=50af192391d8, content=新的研究通路, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Mon May 01 07:14:08 CST 2017, time=2017-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=192026, encodeId=31ac1920268a, content=学习了，谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Apr 30 06:51:08 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191962, encodeId=752f19196245, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 30 00:08:03 CST 2017, time=2017-04-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=191947, encodeId=31fc19194ec4, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=95, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/AiafG5m7kibldQyTnpaQicxg1rnBqFdIGgQBJJs4lR8ibmh91PibzgL7R7pl2HSBjgFeeKRV0mMCvDh49LrgJPCYYvA/132, createdBy=abc91707732, createdName=qjzhai1623, createdTime=Sun Apr 30 00:04:05 CST 2017, time=2017-04-30, status=1, ipAttribution=)]
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Development：周建峰研究组首次揭示GPx4抑制Wnt通路，并在胚胎发育早期及癌症中发挥重要作用

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