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Modulation of thyroid hormone action by mutant thyroid hormone receptors, c-erbAα2 and peroxisome proliferator-activated receptor: evidence for different mechanisms of inhibition

1995; Elsevier BV; Volume: 107; Issue: 1 Linguagem: Inglês

10.1016/0303-7207(94)03422-p

1872-8057

Sibylle C. Meier-Heusler, Xuguang Zhu, Cristiana E. Juge-Aubry, Agnès Pernin, Albert Burger, Sheue-yann Cheng, Christoph A. Meier,

Retinoids in leukemia and cellular processes

Thyroid hormone action is not only determined by hormone availability, but also by target organ sensitivity. A dominant negative interaction is known to occur between thyroid hormone receptors (TRs) and the non-ligand binding splicing variant c-erbAα2 as well as mutant TRβ1 from kindreds with resistance to thyroid hormone. We compared the inhibitory effect of naturally occurring mutant hTRβ1, artificially created hTRα1 mutants, c-erbAα2 and the human peroxisome proliferator-activated receptor (hPPAR) on three prototypic T3-response elements (TREs), TRE-PAL, DR+4 and TRE-LAP. The inhibitory effect of mutant hTRα1 and β1 occurred only on TRE-LAP and to a minor degree on DR+4 when equimolar ratios of mutant/wildtype receptor were present. In contrast, the c-erbAα2 splicing variant and the hPPAR inhibited TR action on all three TREs. Gel mobility shift experiments in the presence of T3 showed increased binding of mutant hTRα1 and β1 only to TRE-LAP compared to the binding of wildtype hTRs, thereby explaining their TRE-selective dominant negative potency. Contrarily, equal amounts of c-erbAα2 or hPPAR protein did not bind to either of the three response elements even in the presence of RXR. Since the TR:RXR heterodimers were only partially displaced from DNA in the presence of excess amounts of c-erbAα2, it is likely that the TRE-unspecific dominant negative action of c-erbAα2 is due in part to competition for DNA-binding and for TR-auxiliary proteins. In contrast, equimolar amounts of hPPAR completely inhibited the DNA-binding of hTRβ1:RXR heterodimers, but not of TR:TR homodimers, suggesting that hPPAR has a higher RXR-binding affinity and is therefore a potent competitor for intranuclear RXR. Since thyroid hormones and peroxisome proliferators regulate in part a similar subset of target genes involved in fatty acid metabolism, these results suggest the possibility of cross-talk among the thyroid hormone and peroxisome proliferator signalling pathways. In summary, the results suggest that thyroid hormone action can be modulated by at least three different mechanisms: (i) increased binding of mutant hTRs to specific TREs; (ii) efficient competition for limiting amounts of RXR through the preferential formation of hPPAR:RXR, rather than TR:RXR heterodimers; and (iii) competition for binding to DNA and to auxiliary proteins other than RXR in the case of c-erbAα2.