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Sci Signal
2011 Nov 01;4197:ra71. doi: 10.1126/scisignal.2001744.
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p53 and microRNA-34 are suppressors of canonical Wnt signaling.
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.
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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.
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Attiyeh,
Chromosome 1p and 11q deletions and outcome in neuroblastoma.
2005, Pubmed
Attiyeh,
Chromosome 1p and 11q deletions and outcome in neuroblastoma.
2005,
Pubmed Bale,
Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p.
1989,
Pubmed Bartel,
MicroRNAs: genomics, biogenesis, mechanism, and function.
2004,
Pubmed Bessard,
Regulation of the specific DNA binding activity of Xenopus laevis p53: evidence for conserved regulation through the carboxy-terminus of the protein.
1998,
Pubmed
,
Xenbase Bommer,
p53-mediated activation of miRNA34 candidate tumor-suppressor genes.
2007,
Pubmed Brummelkamp,
A system for stable expression of short interfering RNAs in mammalian cells.
2002,
Pubmed Burk,
A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells.
2008,
Pubmed Calin,
Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.
2004,
Pubmed Chang,
p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs.
2011,
Pubmed Chang,
Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
2007,
Pubmed Cicalese,
The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells.
2009,
Pubmed Donehower,
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.
1992,
Pubmed Donehower,
20 years studying p53 functions in genetically engineered mice.
2009,
Pubmed Donehower,
Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability.
1995,
Pubmed Eliyahu,
Wild-type p53 can inhibit oncogene-mediated focus formation.
1989,
Pubmed Fearon,
A genetic model for colorectal tumorigenesis.
1990,
Pubmed Finlay,
The p53 proto-oncogene can act as a suppressor of transformation.
1989,
Pubmed Flynt,
Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate.
2007,
Pubmed Funayama,
Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling.
1995,
Pubmed
,
Xenbase Gregory,
The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1.
2008,
Pubmed Grigoryan,
Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice.
2008,
Pubmed Gunther,
Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis.
2003,
Pubmed Hashimi,
MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation.
2009,
Pubmed He,
Identification of c-MYC as a target of the APC pathway.
1998,
Pubmed He,
A microRNA component of the p53 tumour suppressor network.
2007,
Pubmed Jernigan,
Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.
2010,
Pubmed
,
Xenbase Ji,
MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.
2009,
Pubmed Jones,
Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis.
1997,
Pubmed Kennell,
The microRNA miR-8 is a conserved negative regulator of Wnt signaling.
2008,
Pubmed Kim,
A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition.
2011,
Pubmed Kim,
MicroRNA biogenesis: coordinated cropping and dicing.
2005,
Pubmed Kim,
The effects of wild type p53 tumor suppressor gene expression on the normal human cervical epithelial cells or human epidermal keratinocytes transformed with human papillomavirus type 16 DNA.
1995,
Pubmed Knudson,
Mutation and cancer: statistical study of retinoblastoma.
1971,
Pubmed Kumar,
Impaired microRNA processing enhances cellular transformation and tumorigenesis.
2007,
Pubmed Łastowska,
Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data.
2007,
Pubmed Lee,
MicroRNAs in cancer.
2009,
Pubmed Lee,
New class of microRNA targets containing simultaneous 5'-UTR and 3'-UTR interaction sites.
2009,
Pubmed Levine,
The P53 pathway: what questions remain to be explored?
2006,
Pubmed Lodygin,
Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer.
2008,
Pubmed Logan,
The Wnt signaling pathway in development and disease.
2004,
Pubmed Martello,
MicroRNA control of Nodal signalling.
2007,
Pubmed
,
Xenbase Mayr,
Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells.
2009,
Pubmed Miller,
An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival.
2005,
Pubmed Molchadsky,
p53 plays a role in mesenchymal differentiation programs, in a cell fate dependent manner.
2008,
Pubmed Morin,
Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
1997,
Pubmed Nelson,
Convergence of Wnt, beta-catenin, and cadherin pathways.
2004,
Pubmed Nguyen,
WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.
2009,
Pubmed Olivier,
Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.
2003,
Pubmed Ota,
Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1.
2009,
Pubmed Petersen,
Wnt signaling and the polarity of the primary body axis.
2009,
Pubmed Petitjean,
TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes.
2007,
Pubmed Riley,
Transcriptional control of human p53-regulated genes.
2008,
Pubmed Saydam,
Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway.
2009,
Pubmed Schwab,
Genomic instability in 1p and human malignancies.
1996,
Pubmed Tanaka,
Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region.
1993,
Pubmed Thatcher,
Regulation of zebrafish fin regeneration by microRNAs.
2008,
Pubmed Thiele,
AU-rich elements and alternative splicing in the beta-catenin 3'UTR can influence the human beta-catenin mRNA stability.
2006,
Pubmed Thon,
Novel molecular stereotactic biopsy procedures reveal intratumoral homogeneity of loss of heterozygosity of 1p/19q and TP53 mutations in World Health Organization grade II gliomas.
2009,
Pubmed Toyota,
Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer.
2008,
Pubmed van de Wetering,
The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
2002,
Pubmed Wan,
LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Gα(s).
2011,
Pubmed Watanabe,
Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas.
2002,
Pubmed Wei,
The MYCN oncogene is a direct target of miR-34a.
2008,
Pubmed Wei,
A global map of p53 transcription-factor binding sites in the human genome.
2006,
Pubmed Welch,
MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells.
2007,
Pubmed Xu,
MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells.
2009,
Pubmed Yamakuchi,
miR-34a repression of SIRT1 regulates apoptosis.
2008,
Pubmed Yook,
Wnt-dependent regulation of the E-cadherin repressor snail.
2005,
Pubmed
,
Xenbase Yook,
A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells.
2006,
Pubmed
