Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes
Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes
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DOI：
10.1101/gad.368706
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发表时间：
2006-06-01
影响因子：
10.5
通讯作者：
Chambon, Pierre
中科院分区：
文献类型：
--
作者：
Calleja, Cecile;Messaddeq, Nadia;Chambon, Pierre
使用遗传学和药理学方法，我们证明了参与抑制事件的RAR γ/RXR α异源二聚体以及参与激活事件的PPAR β（δ）/RXR α异源二聚体都是基底层上角质形成细胞产生层状颗粒（1，G）所需的细胞自主性，这些细胞器有助于形成皮肤渗透性屏障。在激活PPAR β（δ）/RXR α异二聚体时，RXR α具有转录活性，因为其AF-2激活功能是必需的，并且可以被RXR选择性拮抗剂抑制。在阻遏RAR γ/RXR α异二聚体中，RXR α转录活性的诱导从属于RAR γ激动性配体的添加。因此，可能结合并激活与PPAR β（δ）异二聚化的RXR α的配体不能是视黄酸，因为它也会结合RAR γ并缓解RAR γ介导的抑制，从而产生异常的LG。我们的数据还首次表明，RXR转录活性从属于其RAR伴侣在体内起着至关重要的作用，因为它允许RXR在同一细胞内同时起作用，作为抑制的异源二聚化伴侣，以及它们具有转录活性的激活事件。
Using genetic and pharmacological approaches, we demonstrate that both RAR gamma/RXR alpha heterodimers involved in repression events, as well as PPAR beta(delta)/RXR alpha heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (1,G), the organelles instrumental to the formation of the skin permeability barrier. In activating PPAR beta(delta)/RXR alpha heterodimers, RXR alpha is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RAR gamma/RXR alpha heterodimers, induct, ion of the transcriptional activity of RXR alpha is subordinated to the addition of an agonistic ligand for RAR gamma. Thus, the ligand that possibly binds and activates RXR alpha heterodimerized with PPAR beta(delta) cannot be a retinoic acid, as it would also bind RAR gamma and relieve the RAR gamma-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.