Retinoic Acid Receptors

The differentiation and growth arrest of malignant cells produced by retinoic acid are likely mediated by one or more of the two families of retinoic acid receptors (RAR or RXR): RAR a, b, g; and RXR a, b, g (Linney 1992); all belong to the steroid/thyroid hormone family of transcription factors and possess discrete DNA-binding and retinoic acid-binding do mains. As depicted in Fig. 15.3, retinoic acid binds to the RA receptors, causing conformational changes that promote binding to specific cis-acting DNA sequences, which regulate transcription of certain target genes (Reynolds and Lemons 2001). A study of the RAR and RXR families of RA receptors in NB showed that they were expressed in most NB cell lines and primary tumors (Li et al. 1994).While RAR ß was only expressed in 4 of 14 MYCN amplified cell lines, it could be induced by ATRA in most of these cell lines (Li et al. 1994). There was no correlation between resistance to ATRA and the level of RAR or RXR expression; however, higher expression of RARß has been associated with good outcome in NB and RARß over-expression by transfection in

Figure 15.3 a,b

The mechanism of action of retinoids is mediated via zinc-finger transcriptional regulators which function as het-erodimers to regulate promoter activity of certain target genes.The RAR and RXR proteins bind to specific direct repeat DNA sequences (AGGTCA are separated by either two or five nucleotides) in gene promoters, known as retinoic acid response elements,or RARE.a In the absence of ligand,the RAR/RXR heterodimers interact with nuclear co-repressors including N-CoR and SMRT, which in turn bind to a common adapter protein mSin3 which complexes to proteins with his-tone deacetylase activity to repress transcription. b Retinoic acid binds to the RAR portion of the complex causing a conformational change in the RAR and RXR proteins which releases the co-repressor complex and facilitates binding of 9-cis-RA to the RXR protein (the latter enhances the activation response).The transcriptional co-regulator CBP/p300 then binds to the receptor complex and recruits the coactivator protein ACTR, which contains histone acetyltransferase activ-ity,and promotes transcription (Reynolds and Lemons 2001)

creases the responsiveness of some NB cell lines to RA (Cheung et al. 1998). Furthermore, RARb selective agonists mediate growth inhibitory signals in NB cell lines (Giannini et al. 1997); thus, while alterations in RAR or RXR do not appear to be a major resistance mechanism, higher levels of expression of these receptors may enhance sensitivity to re-tinoids.

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