Identification of cyclic adenosine 3',5'-monophosphate response element modulator as an activator of the human sodium/iodide symporter upstream enhancer.
The lack of Na(+)/I(-) symporter (NIS) gene expression in some thyroid cancer patients has been a major hurdle that limits the efficacy of standard radioactive iodide therapy. The molecular mechanism that contributes to low NIS expression is not well understood. Activated NIS gene expression is stimulated by thyroid-stimulating hormone-mediated cAMP/protein kinase A signaling through a NIS upstream enhancer (NUE). The cAMP pathway is also stimulated by forskolin. In the current work, we studied the mechanism of transcriptional activation of NIS in normal thyroid cells and thyroid cancer cells. We identified the cAMP response element modulator (CREM) activator as a new component of the transcription complex that is important for NIS gene expression. The CREM complex is seen in the normal thyroid cells and BRAF (V600E) thyroid cancer cells (BHP 17-10) but is missing in rearranged in transformation/papillary thyroid carcinoma-1 rearrangement thyroid cancer cells (BHP 2-7). This complex is believed to be responsible for the loss of NUE activity and reduced NIS expression in the BHP 2-7 cell line. In BHP 2-7 cells, forskolin stimulated the thyroid-specific transcription factor Pax 8, but CREM activator mRNA did not increase, and this produced a small increase in NUE activity. Ectopic expression of CREM activator enhanced activity of the NUE, indicating that CREM is an essential regulator of NIS gene expression.
Fenton
Mike S
MS
Endocrinology Division, Veterans Affairs Greater Los Angeles Healthcare System and Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90073, USA. fenton@ucla.edu
Marion
Kenneth M
KM
Hershman
Jerome M
JM
D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051381:Rats; D027981:Symporters / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics; D015533:Transcriptional Activation; D000099209:Sodium-Iodide Symporters
D005576:Colforsin; D051786:Cyclic AMP Response Element Modulator; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D011506:Proteins; D048493:Proto-Oncogene Proteins B-raf; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C497410:CREM protein, human; C083325:PAX8 protein, human; C079238:alcohol O-acetyltransferase; C482119:BRAF protein, human