CONSTITUTIVE TRANSACTIVATION BY THE THYROID-HORMONE RECEPTOR AND A NOVEL PATTERN OF ACTIVITY OF ITS ONCOGENIC HOMOLOG V-ERBA IN XENOPUS OOCYTES

In Xenopus oocytes, the rat thyroid hormone receptor alpha (rTR alpha) but not its oncogenic homolog v-ErbA, constitutively activated thyroi d hormone (T-3)-responsive reporter genes at four positive thyroid hor mone-responsive elements (TREs). At a subset of the positive TREs test ed, the addition of T-3 resulted in a further enhancement of reporter gene activation. In contrast, both rTR alpha and v-ErbA functioned as constitutive activators when bound to the clone 122 TREs, which are in duced by unliganded Tn in mammalian cells. Therefore, the responses of the ligand-independent activation domains of TR and v-ErbA to cell-sp ecific and TRE-mediated induction are not equivalent. Coexpression of the human retinoid X receptor alpha (hRXR alpha) enhanced both ligand- dependent and ligand-independent activation functions of rTR alpha and human TR beta (hTR beta) at a palindromic TRE (TREp). An endogenous T R activity mediated T-3 induction of TREp, while being repressed by an in vitro-generated dominant negative mutant of TR. T-3-mediated gene activation, by exogenous or endogenous TR, was repressed by v-ErbA at three positive TREs, but not at the TRE from the third intron of the r at GH gene (rGH(3)TRE). Interestingly, preinjection of nuclear protein extract from anterior pituitary cells converted v-ErbA into a constit utive activator at rGH(3)TRE. The pituitary-specific factor Pit-1/GHF- 1 or hRXR alpha did not induce activation by v-ErbA at rGH(3)TRE, sugg esting that the dominant negative phenotype of v-ErbA can be abolished by direct or indirect interactions with other nuclear factors.