Abstract
Small lipophilic hormones such as steroid and thyroid hormone play a crucial role in normal function and development in the central nervous system. Each hormone binds to specific nuclear receptors (NRs) with similar molecular structure, which binds to specific nucleotide sequences located at promoter region of target gene. Upon binding to DNA, NRs recruit several groups of cofactors (coactivators and corepressors) in a time-dependent manner to regulate transcription. By now, at least three coactivator complexes, which associate with transcriptional activation by NRs, have been characterized. Complexes containing p160 coactivator such as SRC-1 contain histone acetyltransferase activity (HAT), which acetylates histone to unfold chromatin, thereby facilitating the binding the basal transcriptional machinery. Other coactivator complex contains ATP-dependent chromatin remodeling factor, which disrupts histone-DNA association in ATP-dependent manner, thereby induces transcription as for HAT protein complexes. There is another group of coactivator, termed as TRAP/DRIP/ARC complex, which may directly facilitates recruitment of RNA polymerase II-containing complex. Furthermore, there are additional cofactors such as CoAA, which may regulate not only transcription but also other gene regulation events such as DNA repair and splicing. Disruption of such cofactor genes induces various abnormalities in brain. In this symposium, protein trafficking of NRs and cofactors will be shown. Animal models to study such cofactor action will be also introduced. [Jpn J Physiol 54 Suppl:S52 (2004)]
