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Oncogenic Ras Blocks the cAMP Pathway and Dedifferentiates Thyroid Cells Via an Impairment of Pax8 Transcriptional Activity

S.E.M.M. European School of Molecular Medicine (M.G.B.) and CEINGE Biotecnologie Avanzate (M.G.B.), 80131 Naples, Italy; and Dipartimento di Biologia e Patologia Cellulare e Molecolare (I.P., R.D.L.), Università di Napoli Federico II, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Roberto Di Lauro, Dipartimento di Biologia Cellulare e Molecolare, Università di Napoli Federico II, Via Pansini 5, 80121 Naples, Italy. E-mail: rdilauro{at}unina.it.

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.