The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation.
RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the beta-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3beta (GSK3beta) phosphorylation, ... thereby reducing GSK3beta-mediated NH(2)-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with beta-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)beta-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3beta complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a beta-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing beta-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells. Silencing of beta-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of beta-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on beta-catenin to stimulate cell proliferation.
Mesh Terms:
Carcinoma, Papillary, Cell Nucleus, Cell Proliferation, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, Cyclin D1, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Phosphotyrosine, Promoter Regions, Genetic, Proto-Oncogene Proteins c-ret, Signal Transduction, TCF Transcription Factors, Thyroid Neoplasms, beta Catenin
Carcinoma, Papillary, Cell Nucleus, Cell Proliferation, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, Cyclin D1, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Phosphotyrosine, Promoter Regions, Genetic, Proto-Oncogene Proteins c-ret, Signal Transduction, TCF Transcription Factors, Thyroid Neoplasms, beta Catenin
Cancer Res.
Date: Mar. 01, 2009
PubMed ID: 19223551
View in: Pubmed Google Scholar
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