The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation.
Cancer Res
; 69(5): 1867-76, 2009 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-19223551
ABSTRACT
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Tiroides
/
Carcinoma Papilar
/
Transducción de Señal
/
Proteínas Proto-Oncogénicas c-ret
/
Beta Catenina
Límite:
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2009
Tipo del documento:
Article
País de afiliación:
Italia