ONCOGENIC RAS BLOCKS THE cAMP PATHWAY AND DE-DIFFERENTIATES THYROID CELLS VIA AN IMPAIRMENT OF PAX8 TRANSCRIPTIONAL ACTIVITY.

A deranged differentiation is often a landmark of transformed cells. We used a thyroid cell line expressing an inducible Ras oncoprotein in order to study the hierarchy of molecular events leading to suppression of thyroid-specific gene expression. We find that, upon Ras activation, there is an immediate global down-regulation of thyroid differentiation, which is associated with an inhibition of the cAMP signaling pathway. We demonstrate that an unusual negative cross talk between Ras oncogene and the cAMP pathway induces inactivation of the transcription factor Pax8 that we propose as a crucial event in Ras-induced dedifferentiation.