BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Academic Article uri icon

Overview

abstract

  • In human papillary thyroid cancers (PTCs), mutations of RET/PTC, NTRK, RAS, or BRAF are found in about two thirds of cases with practically no overlap, providing genetic evidence that constitutive signaling along RET-RAS-BRAF-MAPK is key to their development. The requirement for BRAF in RET/PTC-mediated MAPK activation and gene expression has not been tested functionally. There are three RAF isoforms: ARAF, BRAF, and CRAF. Compared with the others, ARAF is a much weaker stimulator of MAPK. To determine the key RAF isoform mediating RET/PTC-induced ERK phosphorylation, we stably transfected doxycycline-inducible RET/PTC3-expressing thyroid PCCL3 cells with small interfering RNA vectors to induce selective knockdown of BRAF or CRAF. Conditional RET/PTC3 expression induced comparable ERK phosphorylation in CRAF knockdown and control cells but negligible ERK phosphorylation in BRAF knockdown cells. Selective knockdown of BRAF prevented RET/PTC-dependent down-regulation of the sodium iodide symporter, a gene that confers key biological effects of RET/PTC in PTCs. Moreover, microarray analysis revealed numerous RET/PTC-regulated genes showing requirement of BRAF for appropriate expression. These data indicate that BRAF is required for RET/PTC-induced MAPK activation in thyroid cells and support the notion that BRAF inactivation may be an attractive target for PTCs.

publication date

  • October 27, 2005

Research

keywords

  • Carcinoma, Papillary
  • Extracellular Signal-Regulated MAP Kinases
  • Gene Expression Regulation, Neoplastic
  • Oncogene Proteins, Fusion
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-ret
  • Thyroid Neoplasms

Identity

Scopus Document Identifier

  • 30944445020

Digital Object Identifier (DOI)

  • 10.1210/en.2005-0280

PubMed ID

  • 16254036

Additional Document Info

volume

  • 147

issue

  • 2