Using genetic and pharmacological approaches, we demonstrate that both RAR␥/RXR␣ heterodimers involved in repression events, as well as PPAR␤(␦)/RXR␣ heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (LG), the organelles instrumental to the formation of the skin permeability barrier. In activating PPAR␤(␦)/RXR␣ heterodimers, RXR␣ is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RAR␥/RXR␣ heterodimers, induction of the transcriptional activity of RXR␣ is subordinated to the addition of an agonistic ligand for RAR␥. Thus, the ligand that possibly binds and activates RXR␣ heterodimerized with PPAR␤(␦) cannot be a retinoic acid, as it would also bind RAR␥ and relieve the RAR␥-mediated repression, thereby yielding abnormal LGs. Our data also demonstrate for the first time that subordination of RXR transcriptional activity to that of its RAR partner plays a crucial role in vivo, because it allows RXRs to act concomitantly, within the same cell, as heterodimerization partners for repression, as well as for activation events in which they are transcriptionally active.[Keywords: Conditional somatic mutagenesis; RAR␥; PPAR␤ (␦); skin permeability barrier; transcriptional subordination; ichthyosis] Supplemental material is available at http://www.genesdev.org.

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Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.

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Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable chemical and thermal stability and hydrophobic character. These features may allow application of carboranes as a new hydrophobic core structure in biologically active molecules that interact hydrophobically with receptors. We report here the design and synthesis of novel androgen antagonists bearing carborane. The most potent compounds, the arylcarborane derivatives 6e and 6i, exhibited antiandrogenic activity greater than that of the well-known antiandrogen hydroxyflutamide in reporter gene assay using NIH3T3 cells transfected with a human AR expression plasmid, as well as in cell growth inhibition assay using androgen-dependent SC-3 cells. Further development of the potent carborane-containing androgen antagonists described here, having a new skeletal structure and unique characteristics, may yield novel therapeutic agents, especially selective androgen receptor modulators.