[Retinoid signalling pathways]

Retinoids, all-trans-retinoic acid (AT-RA) and its bioisters, exert diverse and profound effects on the growth and differentiation of normal and malignant cells, vertebrate development, and homeostasis. Since their nuclear receptors (RARs: alpha, beta and gamma) were cloned, extensive studies on retinoid signalling at molecular level have elucidated its elaborate mechanisms, by which the expression of a variety of retinoid responsive genes are regulated. Furthermore, discoveries of the second receptor system of retinoid (RXRs: alpha, beta and gamma) and their substantial ligand, 9-cis-retinoic acid (9C-RA), were recently reported. The heterodimer formation between RXR and RAR or other members of the steroid/thyroid hormone receptor superfamily gave us a new aspect of hormonal gene control including retinoids, thyroid hormone, vitamin D3 and others. These heterodimers were showed to bind specific response elements consisted of the direct repeat of consensus sequence (AGATTC) or its related sequences. Differential regulation of retinoid responsive gene by RARs or/and RXRs in vivo is an ongoing subject and the combinatory outcome of subtypes or isotypes of receptors, natural response elements, natural ligands (AT-RA, 9C-RA, or their metabolites) owing to pleiotropic effects of retinoids is being revealed. The anti-malignant effect of retinoids is another important theme. The report of prominent therapeutic effect of AT-RA against APL patients was sensational. In many APL patients, translocation between RAR alpha gene and an oncogenic gene, PML, can be detected, although the roles of their fusion products (RAR alpha-PML and PML-RAR alpha) in APL induction have not been understood. Furthermore, the cross-talk between RAR and AP-1 is thought to give an explanation for the suppressive effects of retinoids against tumor promoters (TPA and others). In those contexts, synthetic retinoids specific for each subtype of RAR or RXR, which will be useful reagents for biological studies and/or excellent therapeutic agents, are being developed. Some RAR subtype-selective compounds including antagonists have been already reported.