RARs and RXRs: evidence for two autonomous transactivation functions (AF-1 and AF-2) and heterodimerization in vivo.

Abstract

We have previously reported that the AB regions of retinoic acid receptors (RARs and RXRs) contain a transcriptional activation function capable of modulating the activity of the ligand‐dependent activation function present in the C‐terminal DE regions of these receptors. However, we could not demonstrate that these AB regions possess an autonomous activation function similar to the AF‐1s found in the AB regions of steroid hormone receptors. Using the mouse CRBPII promoter as a reporter gene, we now report that the AB regions of RAR alpha, beta and gamma, as well as those of RXR alpha and gamma, contain an autonomous, ligand‐independent activation function, AF‐1, which can efficiently synergize with AF‐2s. Moreover, AF‐1s account for the ligand‐independent, constitutive activation of transcription by RXR alpha and gamma. We also show that RARs and RXRs preferentially heterodimerize in solution in cultured cells in vivo, through the dimerization interface present in their E region, irrespective of the presence of all‐trans or 9‐cis retinoic acid. Furthermore, our results indicate that homodimeric interactions are not observed in cultured cells in vivo under conditions where heterodimeric interactions readily occur, which is in agreement with previous observations showing the preferential binding of RAR‐RXR heterodimers to RA response elements in vitro.

Functional specificity of the two retinoic acid receptor RAR and RXR families in myogenesis

“…It is interesting to note that, in absence of RA, mutated receptors reduced the proliferative capacity of C2 cells, a result also obtained with C2 cells overexpressing intact RAR or RXR (Figure 2 and data not shown). This observation could be explained by the ligandindependent transactivation function (AF-1) contained within the A/B region of these wild type and mutated retinoic acid receptors (Nagpal et al, 1992(Nagpal et al, , 1993. These results demonstrate that in C2 cells expression of dnRAR or dnRXR leads to inhibition of RAinduced growth arrest.…”

The impact of differential binding of wild-type RARα, PML-, PLZF- and NPM-RARα fusion proteins towards transcriptional co-activator, RIP-140, on retinoic acid responses in acute promyelocytic leukemia

“…This consistently suggests that altered binding activities of APL-associated fusion proteins toward RAREs of the target genes may deregulate the gene expression that are tightly regulated by nuclear hormone receptor family. 18,38,39 Formation of RXR heterodimers is essential for RAR, TR, VDR and PPAR to have efficient binding to their response elements. 8,40,41 Our data show that NPM-RAR␣, like PML-and PLZF-RAR␣, can dimerize with RXR␣ to form heterodimers that bind to RAREs.…”

Growth inhibition in clonal subpopulations of a human epithelioid sarcoma cell line by retinoic acid and tumour necrosis factor alpha

“…The uncoupling of growth inhibition and differentiation induction observed in GRU-1A and GRU-1B after exposure to RA could result from the complexity of RA signal transduction pathways. Thus, receptor heterodimerisation, which has recently been reported to occur between RARs and RXRs (Marks et al, 1992;Nagpal et al, 1993), may result in multiple mutually distinct receptors, each of which presumably activates specific target genes in the regulation of proliferation and differentiation.…”