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Oncogene :上海生科院阐明 Hippo 通路关键转录因子 TEAD4 特异性结合 DNA 机制

2017-04-19 佚名 上海生命科学研究院

4月5日,国际学术期刊 Oncogene 在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所 / 分子细胞科学卓越创新中心周兆才研究组的最新研究成果 DNA-binding mechanism of the Hippo pathway transcription factor TEAD4。该研究在原子水平上阐明了 Hippo 信号通路下游关键转录因子 TEAD4 特异性识别结合



4月5日,国际学术期刊 Oncogene 在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所 / 分子细胞科学卓越创新中心周兆才研究组的最新研究成果 DNA-binding mechanism of the Hippo pathway transcription factor TEAD4。该研究在原子水平上阐明了 Hippo 信号通路下游关键转录因子 TEAD4 特异性识别结合 DNA 的机制。助理研究员史竹兵和硕士研究生何峰是该论文共同第一作者。

Hippo 信号通路在生物个体发育特别是组织器官大小调控过程中具有关键功能,同时在肿瘤发生及免疫应答过程中发挥十分重要的作用。周兆才研究组长期致力于肿瘤发生及免疫应答的分子细胞信号机制研究,近期一系列工作揭示了 Hippo、TLR 等信号通路在胃肠道恶性肿瘤及免疫应答中的机制与功能,发现了多个新的疾病诊疗标识物及药物靶标(Nature Communications 2017; Nature Immunology 2015; EMBO Journal 2015; Cancer Cell 2014; Cell Research 2014)。

研究组此前发现了 Hippo-YAP 信号通路调控胃癌发生发展的新机制,鉴定了 VGLL4 作为 YAP 天然拮抗因子对于胃癌诊疗的潜在应用价值,并发展了治疗性多肽(Cancer Cell, 2014);最近又发现了 Hippo 与 Wnt 通路间的互作新模式,并揭示了 VGLL4 靶向两者核内互作共调控 Hippo、Wnt 通路从而抑制结肠癌的功能作用 (Nature Communications, 2017)。在此基础上,新的工作主要通过结构生物学、生物化学等技术方法,深入解析了 Hippo 通路下游关键转录因子 TEAD4 特异性识别结合 DNA 的机制,发现 TEAD4 的 alpha3 螺旋决定了识别 DNA 的特异性;而其相互作用界面主要由两个位点构成,分别对应于所识别 DNA 的大沟与小沟;针对其中任一位点的突变会使得 TEAD4 在靶基因启动子上的占有率显着下降,大大阻碍 YAP 诱导的 TEAD4 激活与靶基因转录,抑制胃癌细胞生长。

生化与细胞所研究员周金秋和景乃禾对此项工作提供了大力支持与帮助。该工作得到了中科院战略性先导专项(B 类)“细胞命运可塑性的分子基础与调控”、国家自然科学基金委以及上海市的经费资助,相关数据收集得到国家蛋白质科学设施 (上海) 和生化与细胞所分子生物学平台的支持。

原始出处:

Shi Z,He F,Chen M, et al.DNA-binding mechanism of the Hippo pathway transcription factor TEAD4. Oncogene, 2017. DOI: 10.1038/onc.2017.24

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    2018-03-14 mjldent
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    2017-05-02 cy0324
  5. [GetPortalCommentsPageByObjectIdResponse(id=1967922, encodeId=e2bc196e922c4, content=<a href='/topic/show?id=7463199556c' target=_blank style='color:#2F92EE;'>#上海生科院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=98, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=19955, encryptionId=7463199556c, topicName=上海生科院)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0045169, createdName=木头人513, createdTime=Tue Nov 28 01:33:00 CST 2017, time=2017-11-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1747234, encodeId=504d1e4723493, content=<a href='/topic/show?id=832e93345c3' target=_blank style='color:#2F92EE;'>#转录#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=93345, encryptionId=832e93345c3, topicName=转录)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=58df35929710, createdName=mjldent, createdTime=Wed Mar 14 18:33:00 CST 2018, time=2018-03-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1935415, encodeId=dbb5193541583, content=<a href='/topic/show?id=db231e242d1' target=_blank style='color:#2F92EE;'>#TEA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17242, encryptionId=db231e242d1, topicName=TEA)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83erCiat0j36p5MejdM9yCLtcVcY8WS5VIKuCMqXFNs56U6iacZib5CJvh6mVxGERicM6ZAkl91jMgpcDrw/132, createdBy=37622500012, createdName=ms2999106592497887, createdTime=Wed Apr 19 19:33:00 CST 2017, time=2017-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2048814, encodeId=bf992048814be, content=<a href='/topic/show?id=4363e929ad' target=_blank style='color:#2F92EE;'>#Gene#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7929, encryptionId=4363e929ad, topicName=Gene)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=63a4277, createdName=cy0324, createdTime=Tue May 02 23:33:00 CST 2017, time=2017-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=189638, encodeId=b68f189638db, content=学习了!, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20170803/IMG5982F7A3DBB3C1061.jpg, createdBy=0ba51605600, createdName=Jianghuiqin, createdTime=Sat Apr 22 14:48:26 CST 2017, time=2017-04-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1537463, encodeId=687c153e463ae, content=<a href='/topic/show?id=798a93348bb' target=_blank style='color:#2F92EE;'>#转录因子#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=93348, encryptionId=798a93348bb, topicName=转录因子)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b8c712868269, createdName=lanyan20020090, createdTime=Thu Apr 20 17:33:00 CST 2017, time=2017-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1558067, encodeId=d86a155806e56, content=<a href='/topic/show?id=2f1c13349e7' target=_blank style='color:#2F92EE;'>#Oncogene#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13349, encryptionId=2f1c13349e7, topicName=Oncogene)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=154614942533, createdName=zsyan, createdTime=Thu Apr 20 17:33:00 CST 2017, time=2017-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1899118, encodeId=429e189911829, content=<a href='/topic/show?id=6f746e94170' target=_blank style='color:#2F92EE;'>#特异性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=67941, encryptionId=6f746e94170, topicName=特异性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=dc7a157, createdName=jinweidong, createdTime=Fri Mar 09 14:33:00 CST 2018, time=2018-03-09, status=1, ipAttribution=)]
    2017-04-22 Jianghuiqin

    学习了!

    0

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    2017-04-20 zsyan
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