RT Journal Article
SR Electronic
T1 p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra71
OP ra71
DO 10.1126/scisignal.2001744
VO 4
IS 197
A1 Kim, Nam Hee
A1 Kim, Hyun Sil
A1 Kim, Nam-Gyun
A1 Lee, Inhan
A1 Choi, Hyung-Seok
A1 Li, Xiao-Yan
A1 Kang, Shi Eun
A1 Cha, So Young
A1 Ryu, Joo Kyung
A1 Na, Jung Min
A1 Park, Changbum
A1 Kim, Kunhong
A1 Lee, Sanghyuk
A1 Gumbiner, Barry M.
A1 Yook, Jong In
A1 Weiss, Stephen J.
YR 2011
UL http://stke.sciencemag.org/content/4/197/ra71.abstract
AB 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.