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p53 and microRNA-34 are suppressors of canonical Wnt signaling

Authors
 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 
Citation
 SCIENCE SIGNALING, Vol.4(197) : 71, 2011 
Journal Title
SCIENCE SIGNALING
ISSN
 1937-9145 
Issue Date
2011
MeSH
3' Untranslated Regions/genetics ; Animals ; Base Sequence ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cells, Cultured ; Chick Embryo ; Child ; Embryo, Nonmammalian/embryology ; Embryo, Nonmammalian/metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation* ; HEK293 Cells ; Humans ; Mice ; MicroRNAs/genetics* ; MicroRNAs/metabolism ; Mutation ; Neuroblastoma/genetics ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; RNA Interference ; TCF Transcription Factors/genetics ; TCF Transcription Factors/metabolism ; Tumor Suppressor Protein p53/genetics* ; Tumor Suppressor Protein p53/metabolism ; Wnt Signaling Pathway/genetics* ; Wnt1 Protein/genetics ; Wnt1 Protein/metabolism ; Xenopus laevis ; beta Catenin/genetics ; beta Catenin/metabolism
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.
Files in This Item:
T201104043.pdf Download
DOI
10.1126/scisignal.2001744
Appears in Collections:
2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shi Eun(강시은)
Kim, Kun Hong(김건홍) ORCID logo https://orcid.org/0000-0001-5639-6372
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Ryu, Ju Kyoung(유주경)
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Cha, So Young(차소영) ORCID logo https://orcid.org/0000-0002-2810-3883
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/94627
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