p53 and microRNA-34 are suppressors of canonical Wnt signaling.
p53 and microRNA-34 are suppressors of canonical Wnt signaling.
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DOI：
10.1126/scisignal.2001744
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发表时间：
2011-11-01
影响因子：
7.3
通讯作者：
Weiss SJ
中科院分区：
文献类型：
--
作者：
Kim NH;Kim HS;Kim NG;Lee I;Choi HS;Li XY;Kang SE;Cha SY;Ryu JK;Na JM;Park C;Kim K;Lee S;Gumbiner BM;Yook JI;Weiss SJ
虽然p53功能的丧失和经典Wnt信号级联的激活在癌症中经常偶联，但这两种途径之间的联系仍不清楚。我们在此报道了p53反式激活miRNA-34（miR-34），其通过靶向Wnt通路调控基因网络中一组高度保守靶标的非翻译区（UTR）来抑制β-连环蛋白-T细胞因子/淋巴增强因子（TCF/LEF）复合物的转录活性。p53功能的丧失通过miR-34与靶UTR的特异性相互作用增加经典Wnt信号传导，而miR-34缺失减轻p53介导的Wnt抑制。此外，反映乳腺癌和儿科神经母细胞瘤患者中β-连环蛋白-TCF/LEF转录活性状态的基因表达特征与p53和miR-34功能状态密切相关。p53或miR-34的缺失通过触发结直肠癌细胞的Wnt依赖性组织侵袭活性而促进肿瘤进展。此外，在发育过程中，miR-34与β-catenin UTR的相互作用决定了爪蟾体轴极性和Wnt依赖性基因模式。这些数据提供了对p53-miR-34网络在发育生物体和人类癌症中抑制经典Wnt信号级联的机制的深入了解。
Although loss of p53 function and activation of canonical Wnt signaling cascades are frequently coupled in cancer, the links between these two pathways remain unclear. We report here that p53 transactivates miRNA-34 (miR-34), which suppresses the transcriptional activity of β-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of highly-conserved targets in a network of Wnt pathway-regulated genes. Loss of p53 function increases canonical Wnt signaling through miR-34-specific interactions with target UTRs, whereas miR-34 depletion relieves p53-mediated Wnt repression. Further, gene expression signatures reflecting the status of β-catenin-TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients are closely associated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent, tissue-invasive activity of colorectal cancer cells. Further, during development, miR-34 interactions with the β-catenin UTR determine Xenopus body axis polarity and Wnt-dependent gene patterning. These data provide insight into the mechanisms by which a p53-miR-34 network restrains canonical Wnt signaling cascades in developing organisms and human cancer.
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影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
microRNA miR-34抑制人类胰腺癌肿瘤发射细胞。
影响因子：
3.7
作者：
Ji Q;Hao X;Zhang M;Tang W;Yang M;Li L;Xiang D;Desano JT;Bommer GT;Fan D;Fearon ER;Lawrence TS;Xu L
通讯作者：
Xu L
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
20.3
作者：
Hashimi, Sara T.;Fulcher, Jennifer A.;Lee, Benhur
通讯作者：
Lee, Benhur