A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity
0301 basic medicine
Skin Neoplasms
Caveolin 1
Transgenic
GTP Phosphohydrolases
Glycogen Synthase Kinase 3
Mice
Phosphatidylinositol 3-Kinases
2.1 Biological and endogenous factors
Aetiology
Melanoma
beta Catenin
Cancer
Feedback, Physiological
Microscopy
0303 health sciences
Tumor
Blotting
Biological Sciences
Prognosis
Cadherins
Immunohistochemistry
3. Good health
Melanocytes
Western
Transcriptional Activation
570
Physiological
Blotting, Western
610
Mice, Transgenic
612
Fluorescence
Article
Cell Line
Feedback
03 medical and health sciences
Cell Line, Tumor
Genetics
Animals
Humans
Glycogen Synthase Kinase 3 beta
Biomedical and Clinical Sciences
PTEN Phosphohydrolase
Membrane Proteins
ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre
MicroRNAs
Microscopy, Fluorescence
Biochemistry and Cell Biology
PRIMARY CUTANEOUS MELANOMA TUMOR-SUPPRESSOR GENE METASTATIC MELANOMA CELL-MIGRATION CANCER CELLS ACTIVATION SENESCENCE EXPRESSION PROLIFERATION INVASION
Proto-Oncogene Proteins c-akt
DOI:
10.1038/ncomms9093
Publication Date:
2015-08-26T10:27:09Z
AUTHORS (19)
ABSTRACT
AbstractLoss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K–AKT–GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRASQ61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β–catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.
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