Fig. 7. Model of L-GILZ upregulation in anaplastic thyroid cancer cells treated with MAPK inhibitors.

In healthy thyroid cells and many differentiated thyroid carcinomas (DTC), TSH triggers TSH receptor/cAMP/PKA pathways thus activating CREB and regulating thyroid cell differentiation and proliferation. In anaplastic thyroid carcinoma (ATC), mutations in Ras or BRAF induce the constitutive activation of MAPK signaling, leading to transcription factor activation and production of proliferative proteins. Pharmacological inhibition of hyperactivated BRAF or MEK induces the inhibition of MAPK activity, as well as phosphorylation of p38, which leads to CREB activation, increase of L-GILZ transcription through CREB binding to the L-GILZ promoter, and the upregulation of L-GILZ protein expression. Ultimately, L-GILZ contributes to the antiproliferative effects of MAPK inhibitors