Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma.

Abstract

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 of MST1 tumor suppressor pathways, is inactivated by hypermethylation of its promoter region in 20 to 32% of PTC. However, in PTC without RASSF1A methylation, the regulatory mechanisms of RASSF1A-MST1 pathways remain to be elucidated, and the functional cooperation or cross regulation between BRAF(V600E) and MST1,which activates Foxo3,has not been investigated.

METHODOLOGY/PRINCIPAL FINDINGS:

The negative regulators of the cell cycle, p21 and p27, are strongly induced by transcriptional activation of FoxO3 in BRAF(V600E) positive thyroid cancer cells. The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway. Interestingly, introduction of BRAF(V600E)markedly abolished FoxO3 transactivation and resulted in the suppression of p21 and p27 expression. The suppression of FoxO3 transactivation by BRAF(V600E)is strongly increased by coexpression of MST1 but it is not observed in the cells in which MST1, but not MST2,is silenced. Mechanistically, BRAF(V600E)was able to bind to the C-terminal region of MST1 and resulted in the suppression of MST1 kinase activities. The induction of the G1-checkpoint CDK inhibitors, p21 and p27,by the RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition of BRAF(V600E) inhibits the apoptotic processes through the inactivation of MST1. Transgenic induction of BRAF(V600E)in the thyroid gland results in cancers resembling human papillary thyroid cancers. The development of BRAF(V600E)transgenic mice with the MST1 knockout background showed that these mice had abundant foci of poorly differentiated carcinomas and large areas without follicular architecture or colloid formation.

CONCLUSIONS/SIGNIFICANCE:

The results of this study revealed that the oncogenic effect of BRAF(V600E) is associated with the inhibition of MST1 tumor suppressor pathways, and that the activity of RASSF1A-MST1-FoxO3 pathways determines the phenotypes of BRAF(V600E) tumors.

• Authors: Seong Jin Lee, Min Hee Lee, Dong Wook Kim, Seongeun Lee, Songmei Huang, Min Jeong Ryu, Yong Kyung Kim, Sung Jin Kim, Soung Jung Kim, Jung Hwan Hwang, Sangphil Oh, Heeyeong Cho, Jin Man Kim, Dae-Sik Lim, Young Suk Jo, Minho Shong
• Journal: PloS one (PLoS One) Vol. 6 Issue 1 Pg. e16180 (Jan 13 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21249150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Intracellular Signaling Peptides and Proteins
• RASSF1 protein, human
• Tumor Suppressor Proteins
• STK4 protein, human
• BRAF protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Apoptosis
• Carcinoma
• Carcinoma, Papillary
• Cell Cycle Proteins
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins
• Mice
• Mutation, Missense
• Neoplasms, Experimental
• Phenotype
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Receptor Cross-Talk (physiology)
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (metabolism, pathology)
• Tumor Suppressor Proteins (antagonists & inhibitors, metabolism)