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 of neuroblastoma N2a-β cells that express the thyroid hormone receptor (TR) β1 isoform. c-Myc is required for cell cycle progression, and this study 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 identified within the first exon between nucleotides +237 and +268. The TRE is adjacent to the binding site for the transcriptional repressor CCCTC binding factor and maps precisely within the region of RNA polymerase II pausing and release, suggesting a direct implication of TR on premature termination of transcription. Furthermore, the TRE confers repression by T3 to an heterologous promoter only when inserted downstream of the transcription initiation site. Binding of CCCTC binding factor and TR to their cognate sites in the region of transcriptional attenuation, as well as direct interactions between both factors, could facilitate the formation of a repressor complex and the inhibition of c-myc gene expression. These studies provide insight into mechanisms by which TR mediate transcriptional repression and contribute to the understanding of the important effects of thyroid hormones on growth and differentiation of neuronal cells.This work was supported by Grants PM97-0135 from the Dirección General de Enseñanza Superior and 08.1/0032 from the Comunidad de Madrid.Peer Reviewe