Oncogenic ras blocks the cAMP pathway and dedifferentiates 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.
Baratta
Maria Giuseppina
MG
S.E.M.M. European School of Molecular Medicine, CEINGE Biotecnologie Avanzate, Naples, Italy.
Porreca
Immacolata
I
Di Lauro
Roberto
R
D000818:Animals; D054337:Cell Dedifferentiation; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D007700:Kinetics; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D011989:Receptors, Thyrotropin / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology*; D014158:Transcription, Genetic; D000099209:Sodium-Iodide Symporters
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D011989:Receptors, Thyrotropin; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C499497:Pax8 protein, rat