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PI3K Is Involved in the IGF-I Inhibition of TSH-Induced Sodium/Iodide Symporter Gene Expression

Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain E-28029

Address all correspondence and requests for reprints to: Dr. Pilar Santisteban, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier, 4, E-28029 Madrid, Spain. E-mail: psantisteban{at}iib.uam.es

Here we studied the role of IGF-I on the regulation of the sodium/iodide symporter (NIS) gene expression in FRTL-5 thyroid cells. IGF-I did not modify NIS mRNA levels but inhibited TSH- and forskolin-induced NIS mRNA expression in a dose-dependent manner. We explored the signaling pathways by which IGF-I mediates the repression of NIS expression. Inhibition of either the MAPK kinase or PKC activities had no effect. Interestingly, inhibition of PI3K blocked IGF-I repression of TSHinduced NIS mRNA and protein levels. This effect takes place at the transcriptional level, as IGF-I inhibited TSH-induced transcription of a luciferase reporter construct containing a 2.8-kb DNA fragment of the rat NIS promoter. The inhibitory effect of IGF-I on the NIS promoter was blocked by the PI3K inhibitor LY294002 and was mimicked by overexpression of a vector harboring the constitutively activated catalytic subunit of PI3K. Using internal deletions of the NIS promoter, we defined a region from -1,947 to -1,152 responsible for the observed IGF-I/PI3K inhibitory effect. When fused to a heterologous promoter, this region inhibits transcription in response to IGF-I. These results demonstrate a central role for PI3K in the repression of NIS gene transcription by IGF-I and suggest the existence, within the above defined promoter region, of putative PI3K-responsive elements.

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