E. Jeannin et al., TRANSCRIPTIONAL REGULATORY PATTERNS OF THE MYELIN BASIC-PROTEIN AND MALIC ENZYME GENES BY THE THYROID-HORMONE RECEPTORS ALPHA-1 AND BETA-1, The Journal of biological chemistry, 273(37), 1998, pp. 24239-24248
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.