title: p53 and microRNA-34 are suppressors of canonical Wnt signaling.
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.
authors: Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul 120-752, Korea.
authors: Nam Hee
authors: NH
authors: Kim
authors: Hyun Sil
authors: HS
authors: Kim
authors: Nam-Gyun
authors: NG
authors: Kim
authors: Inhan
authors: I
authors: Lee
authors: Hyung-Seok
authors: HS
authors: Choi
authors: Xiao-Yan
authors: XY
authors: Li
authors: Shi Eun
authors: SE
authors: Kang
authors: So Young
authors: SY
authors: Cha
authors: Joo Kyung
authors: JK
authors: Ryu
authors: Jung Min
authors: JM
authors: Na
authors: Changbum
authors: C
authors: Park
authors: Kunhong
authors: K
authors: Kim
authors: Sanghyuk
authors: S
authors: Lee
authors: Barry M
authors: BM
authors: Gumbiner
authors: Jong In
authors: JI
authors: Yook
authors: Stephen J
authors: SJ
authors: Weiss
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D002648:Child; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D051820:TCF Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D051176:beta Catenin