Fig. 3.

TSH signaling inhibits BRAFV600E-induced senescence through phosphorylation of ERK1/2. TSH thyroid-stimulating hormone; TSHR thyroid-stimulating hormone receptor; MnSOD manganese superoxide dismutase; ROS reactive oxygen species; DUSP6 dual-specific phosphatase 6. (a) Mitogenic stimulus activates RAS which in turn activates mutant BRAF protein and triggers the MAPK/ERK signaling cascade which results in the phosphorylation of ERK1/2. Phosphorylated ERK1/2 (p-ERK1/2) inhibits RAS activity and hence inhibits RAS-dependent AKT signaling, which if activated, produces oncogenic proteins such as c-Myc. This feedback inhibition induces OIS in BRAFV600E PTC thyrocytes. (b) Once serum TSH increases, the coupled effect of increased number of TSHR (unique phenotype of BRAFV600E) on the thyrocyte membrane and increased TSH triggers increased TSH/TSHR signaling which results in increased expression of MnSOD. MnSOD normally inhibits the levels of ROS and ROS (scavenged by MnSOD) in turn inhibits the levels of DUSP6. The increase in MnSOD relieves the inhibition on DUSP6 by ROS resulting in increased levels of DUSP6. High levels of DUSP6 cause the dephosphorylation of p-ERK1/2 (the result of MAPK/ERK signaling), hence lifting the feedback inhibition on RAS. The reactivation of RAS activates the RAS-dependent AKT signaling pathway resulting in the production of oncogenic proteins such as c-Myc leading progression into malignancy