Cross-Regulation between Oncogenic BRAFV600E Kinase and the MST1 Pathway in Papillary Thyroid Carcinoma

摘要: Background The BRAF(V600E) mutation leading to constitutive signaling of MEK-ERK pathways causes papillary thyroid cancer (PTC). Ras association domain family 1A (RASSF1A), which is an important regulator MST1 tumor suppressor pathways, inactivated by hypermethylation its promoter region in 20 32% PTC. However, PTC without RASSF1A methylation, the regulatory mechanisms RASSF1A-MST1 remain be elucidated, and functional cooperation or cross regulation between MST1,which activates Foxo3,has not been investigated. Methodology/principal findings negative regulators cell cycle, p21 p27, are strongly induced transcriptional activation FoxO3 positive cells. transactivation augmented pathway. Interestingly, introduction BRAF(V600E)markedly abolished resulted suppression p27 expression. BRAF(V600E)is increased coexpression but it observed cells MST1, MST2,is silenced. Mechanistically, BRAF(V600E)was able bind C-terminal kinase activities. induction G1-checkpoint CDK inhibitors, p27,by RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition inhibits apoptotic processes through inactivation MST1. Transgenic BRAF(V600E)in gland results cancers resembling human cancers. development BRAF(V600E)transgenic mice with knockout background showed that these had abundant foci poorly differentiated carcinomas large areas follicular architecture colloid formation. Conclusions/significance this study revealed oncogenic effect associated inhibition activity determines phenotypes tumors.