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Sci. Signal., 1 November 2011
Vol. 4, Issue 197, p. ra71
[DOI: 10.1126/scisignal.2001744]

RESEARCH ARTICLES

p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling

Nam Hee Kim1*, Hyun Sil Kim1*, Nam-Gyun Kim2, Inhan Lee3, Hyung-Seok Choi4{dagger}, Xiao-Yan Li5, Shi Eun Kang1, So Young Cha1, Joo Kyung Ryu1, Jung Min Na1, Changbum Park1, Kunhong Kim6, Sanghyuk Lee4,7, Barry M. Gumbiner2, Jong In Yook1{ddagger}, and Stephen J. Weiss5

1 Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul 120-752, Korea.
2 Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
3 miRcore, 2929 Plymouth Road, Ann Arbor, MI 48105, USA.
4 Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
5 Division of Molecular Medicine and Genetics, Department of Internal Medicine and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
6 Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science of Yonsei University, Center for Chronic Metabolic Disease Research, School of Medicine, Yonsei University, Seoul 120-752, Korea.
7 Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.

* These authors contributed equally to this work.

{dagger} Present address: Bio and Health Group, Future IT R&D Lab., LG Electronics Inc., 221 Yangjae-Dong, Seocho-Gu, Seoul 137-130, Korea.

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.

{ddagger} To whom correspondence should be addressed. E-mail: jiyook{at}yuhs.ac

Citation: N. H. Kim, H. S. Kim, N.-G. Kim, I. Lee, H.-S. Choi, X.-Y. Li, S. E. Kang, S. Y. Cha, J. K. Ryu, J. M. Na, C. Park, K. Kim, S. Lee, B. M. Gumbiner, J. I. Yook, S. J. Weiss, p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling. Sci. Signal. 4, ra71 (2011).

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