Endocrine Abstracts

Nuclear receptors such as the thyroid hormone receptors (TR α and β) or vitamin D receptors (VDR) regulate gene expression by binding to DNA as heterodimers with the retinoid X receptor (RXR). Their effects on transcription are mediated by the recruitment of coregulators (coactivators and corepressors). The C-terminal AF-2 receptor domains are required for coactivators recruitment. The RXR ligand (9-cis-RA) cooperates with the ligand of its partner receptor to recruit coactivators and to stimulate ligand-dependent transcription. Furthermore, 9-cis-RA overcomes the defective activity of VDR or TR AF-2 mutants, and restores recruitment of mutant p160 coactivators. In contrast, the RXR AF-2 domain plays an inhibitory role on corepressors recruitment by these heterodimers. Whereas unliganded TR/RXR heterodimers bind the corepressors NCoR and SMRT, binding of an agonist to VDR allows association of the corepressors to RXR. Therefore, binding of either agonist results in a linked conformational change in the partner receptor that influences coregulator recruitment to the target promoter.

Nuclear receptors can also influence gene expression by regulating the activity of other signalling pathways. For instance, TRs inhibit ras-induced transcription and proliferation, block fibroblast transformation by the oncogene and suppress tumor formation in nude mice. Furthermore, expression of TRβ in hepatoma and breast cancer cells delays tumor appearance in nude mice and gives rise to tumors with a more differentiated phenotype. The receptor also has a very potent inhibitory effect on lung metastasis formation. TRβ-expressing cells show a reduced invasiveness in ‘in vitro’ assays and are unable to proliferate in response to growth factors. In a model of ras-dependent chemical skin carcinogenesis, the number of tumors developed is smaller in TRα^−/−/TRβ^−/−mice. However, tumor volume increases more rapidly in the K.O. animals and some of the tumors show signs of progression to carcinoma. These results show the existence of a relevant cross-talk between the ras oncogene and TR, and define this receptor as a potent suppressor of cell transformation and tumorigenesis.