LOSS OF RETINOIC ACID RECEPTOR-GAMMA FUNCTION IN F9 CELLS BY GENE DISRUPTION RESULTS IN ABERRANT HOXA-1 EXPRESSION AND DIFFERENTIATION UPON RETINOIC ACID TREATMENT
LOSS OF RETINOIC ACID RECEPTOR-GAMMA FUNCTION IN F9 CELLS BY GENE DISRUPTION RESULTS IN ABERRANT HOXA-1 EXPRESSION AND DIFFERENTIATION UPON RETINOIC ACID TREATMENT
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DOI：
10.1073/pnas.90.20.9601
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发表时间：
1993-10-15
影响因子：
11.1
通讯作者：
GUDAS, LJ
中科院分区：
文献类型：
--
作者：
BOYLAN, JF;LOHNES, D;GUDAS, LJ
视黄酸（RA）信号转导被认为是通过几个高亲和力的核受体[RA受体（RAR）和类维生素A X受体]介导的，这些受体是类固醇/甲状腺/维生素D超家族的成员，并作为转录因子发挥作用。为什么存在多个RAR以及三种受体中的每一种都调节哪些基因靶点仍然是发育生物学中引人注目的问题。通过靶向破坏两个RAR γ等位基因，我们已经确定了几个分化特异性基因，这些基因在F9胚胎癌细胞中直接或间接受RAR γ调控。这些包括编码Hoxa-1（Hox-1.6）和细胞外基质蛋白层粘连蛋白B1和IV型胶原（α 1）的基因，所有这些基因在野生型F9胚胎癌细胞中都是RA诱导的，但在RAR γ-/-系中没有显著诱导。相反，编码Hoxb-1（Hox-2.9）和细胞RA结合蛋白II（CRABPII）的转录物在RAR γ-/-系中被RA激活的时间比野生型F9系长。并非所有RA应答基因都异常表达;雷克斯-1、RAR β和RAR β转录物在RAR γ-/-细胞系中受到调节，就像它们在F9野生型细胞中一样。我们的研究结果支持的想法，每个RAR可能会调节不同的RA反应基因的子集，这可以解释，在一定程度上，复杂的调节发育过程中的维甲酸。
Retinoic acid (RA) signal transduction is believed to be mediated through several high-affinity nuclear receptors [RA receptors (RARs) and retinoid X receptors], which are members of the steroid/thyroid/vitamin D superfamily and function as transcription factors. Why multiple RARs exist and what gene targets are regulated by each of the three receptors remain compelling questions in developmental biology. Through targeted disruption of both RARgamma alleles, we have identified several differentiation-specific genes that are regulated either directly or indirectly by RARgamma in F9 embryonal carcinoma cells. These include genes encoding Hoxa-1 (Hox-1.6) and the extracellular matrix proteins laminin B1 and collagen type IV (alpha1), all of which are RA inducible in wild-type F9 embryonal carcinoma cells but are not significantly induced in the RARgamma-/- lines. In contrast, transcripts encoding Hoxb-1 (Hox-2.9) and cellular RA binding protein II (CRABPII) are activated by RA for a longer period of time in the RARgamma-/- lines compared to the wild-type F9 line. Not all RA-responsive genes are aberrantly expressed; Rex-1, RARbeta, and SPARC transcripts are regulated in the RARgamma-/- lines as they are in F9 wild-type cells. Our results support the idea that each RAR may regulate different subsets of RA-responsive genes, which may explain, in part, the complex regulation of developmental processes by retinoids.