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Submitted on March 10, 2005
Accepted on October 17, 2005
Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati Ohio 45267, USA; Department of Chemistry and Biotechnology, University of Tokyo School of Engineering, Hongo Tokyo 113-8656, Japan
* To whom correspondence should be addressed. E-mail: James.Fagin{at}uc.edu.
In human papillary thyroid cancers (PTCs), mutations of RET/PTC, NTRK, RAS or BRAF are found in about 2/3 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 siRNA 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 downregulation 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.
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