An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells

The thyroid hormone (T3) blocks proliferation and induces differentiation o f neuroblastoma N2a-beta cells that express the thyroid hormone receptor (T R) beta 1 isoform. c-Myc is required for cell cycle progression, and this s tudy shows that T3-induced neuronal differentiation is preceded by a rapid decrease of c-myc gene expression. A negative T3 responsive element (TRE), arranged as an inverted palindrome spaced by three nucleotides, has been id entified within the first exon between nucleotides +237 and +268, The TRE i s adjacent to the binding site for the transcriptional repressor CCCTC bind ing factor and maps precisely within the region of RNA polymerase II pausin g and release, suggesting a direct implication of TR on premature terminati on of transcription. Furthermore, the TRE confers repression by T3 to an he terologous promoter only when inserted downstream of the transcription init iation site. Binding of CCCTC binding factor and TR to their cognate sites in the region of transcriptional attenuation, as well as direct interaction s between both factors, could facilitate the formation of a repressor compl ex and the inhibition of c-myc gene expression. These studies provide insig ht into mechanisms by which TR mediate transcriptional repression and contr ibute to the understanding of the important effects bf thyroid hormones on growth and differentiation of neuronal cells.