RET-mediated CD44 proteolysis promotes autonomous proliferation of thyroid cells
Tamburrino, Anna (2008) RET-mediated CD44 proteolysis promotes autonomous proliferation of thyroid cells. [Tesi di dottorato] (Inedito)
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This dissertation addresses signaling mechanisms involved in thyroid carcinoma formation, with a view of identifying novel levels for therapeutic intervention. In this frame, appended manuscripts II, III and IV focus on the functional characterization of a novel BRAF mutation and on molecular targeting of RET or BRAF pathways in thyroid cancer. The main body of the dissertation describes a novel signaling mechanism that we have identified in thyroid carcinomas harboring BRAF or RET/PTC oncogenes and that involves CD44. CD44, a cell surface adhesion molecule overexpressed in a wide range of cancer types, undergoes sequential proteolytic cleavage at the extracellular and intramembrane domains. This results in the shedding of the ectodomain (ectoCD44) and in the intracellular release of an intracellular fragment (CD44-ICD). CD44-ICD is translocated to the nucleus and activates gene transcription. Our group has previously demonstrated that CD44 is overexpressed in papillary thyroid carcinoma (PTC) tissue samples and in cell lines harboring RET/PTC or BRAF oncogenes. Here, we show that RET/PTC signaling induces γ-secretase-dependent CD44 proteolysis through the ERK pathway. Chemical blockade of either RET/PTC or MEK abrogates CD44 cleavage. Adoptive overexpression of CD44-ICD stimulates TSH-independent proliferation of thyroid follicular PC cells. CD44-ICD binds to CREB and stimulates CREB-mediated transcription in PC cells by potentiating CREB S133 phosphorylation. Through this mechanism, CD44-ICD up-regulates cyclin D1 expression and proliferation of thyroid cells. Taken together, these findings suggest that ERK kinase pathway-mediated CD44 cleavage sustains proliferation of thyrocytes harboring RET/PTC, RAS or BRAF oncogenes. This novel pathway may provide new molecular targets for therapeutic intervention in thyroid carcinoma.
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