TRANSCRIPTIONAL REGULATORY PATTERNS OF THE MYELIN BASIC-PROTEIN AND MALIC ENZYME GENES BY THE THYROID-HORMONE RECEPTORS ALPHA-1 AND BETA-1

While there is evidence that the two ubiquitously expressed thyroid ho rmone (T3) receptors, TR alpha 1 and TR beta 1, have distinct function al specificities, the mechanism by which they discriminate potential t arget genes remains largely unexplained. In this study, we demonstrate that the thyroid hormone response elements (TRE) from the malic enzym e and myelin basic protein genes (METRE and MBPTRE) respectively, are not functionally equivalent. The METRE which is a direct repeat motif with a 4-base pair gap between the two half-site hexamers binds thyroi d hormone receptor as a heterodimer with 9-cis-retinoic acid receptor (RXR) and mediates a high T3-dependent activation in response to TR al pha 1 or TR beta 1 in NIH3T3 cells. In contrast, the MBPTRE, which con sists of an inverted palindrome formed by two hexamers spaced by 6 bas e pairs, confers an efficient transactivation by TR beta 1 but a poor transactivation by TR alpha 1, While both receptors form heterodimers with RXR on MBPTRE the poor transactivation by TR alpha 1 correlates a lso with its ability to bind efficiently as a monomer, This monomer, w hich is only observed with TR alpha 1 bound to MBPTRE, interacts neith er with N-CoR nor with SEC-I, explaining its functional inefficacy, Ho wever, in Xenopus oocytes, in which RXR proteins are not detectable, t he transactivation mediated by TR alpha 1 and TR beta 1 is equivalent and independent of a RXR supply, raising the question of the identity of the thyroid hormone receptor partner in these cells. Thus, in mamma lian cells, the binding characteristics of TR alpha 1 to MBPTRE (i.e. high monomer binding efficiency and low transactivation activity) migh t explain the particular pattern of T3 responsiveness of MBP gene expr ession during central nervous system development.