p53 and microRNA-34 are suppressors of canonical Wnt signaling

Nam Hee Kim, Hyun Sil Kim, Nam Gyun Kim, Inhan Lee, Hyung Seok Choi, Xiao Yan Li, Shi Eun Kang, So Young Cha, Joo Kyung Ryu, Jung Min Na, Changbum Park, Kunhong Kim, Sanghyuk Lee, Barry M. Gumbiner, Jong In Yook, Stephen J. Weiss

Research output: Contribution to journalArticlepeer-review

242 Scopus citations

Abstract

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 that p53 transactivated microRNA-34 (miR-34), which consequently suppressed the transcriptional activity of β-catenin - T cell factor and lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of conserved targets in a network of genes encoding elements of the Wnt pathway. Loss of p53 function increased canonical Wnt signaling by alleviating miR-34 - specific interactions with target UTRs, and miR-34 depletion relieved p53-mediated Wnt repression. Gene expression signatures reflecting the status of β-catenin - TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients were correlated 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 affected Xenopus body axis polarity and the expression of Wnt-dependent patterning genes. 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.

Original languageEnglish
Article numberra71
JournalScience Signaling
Volume4
Issue number197
DOIs
StatePublished - 1 Nov 2011

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