Activation of the prolactin gene by peroxisome proliferator-activated receptor-α appears to be DNA binding-independent
Activation of the prolactin gene by peroxisome proliferator-activated receptor-α appears to be DNA binding-independent
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DOI：
10.1074/jbc.273.41.26652
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发表时间：
1998-10-09
影响因子：
4.8
通讯作者：
Aranda, A
中科院分区：
文献类型：
--
作者：
Tolón, RM;Castillo, AI;Aranda, A
虽然过氧化物酶体增殖物激活受体（PPARs）的影响主要在脂肪细胞和肝脏中进行了研究，这些受体的广泛分布表明，它们也可能在其他细胞类型中发挥作用，我们目前的证据表明，PPAR激活剂刺激垂体GH4 C1细胞中催乳素基因的表达。非垂体HeLa细胞中的转染试验表明，通过PPAR α刺激催乳素启动子需要转录因子GHF-1（或Pit-1）的存在，近端启动子序列赋予对PPAR α的响应性，并且该受体的激活伴随着对GHF-1的响应而丧失。令人惊讶的是，类维生素A X受体（RXR）的表达消除了由PPARa引起的刺激。此外，赋予PPARa应答性的启动子区域不包含PPARa应答元件。这表明PPARalpha的转录作用可能是由蛋白质-蛋白质相互作用介导的，而不是由PPAR-RXR与启动子的结合介导的。通过体外结合研究证实了PPAR α和GHF-1之间的直接相互作用。与PPAR结合的辅激活因子SRC-1和CREB结合蛋白的表达也增强了催乳素启动子对PPAR α的反应性。此外，CREB结合蛋白还显著增加了GHF-1的激活，并且这两种蛋白在体外结合。因此，在一种情况下，通常通过结合特定DNA序列作为配体依赖性转录因子的受体PPAR α也可以通过与GHF-1和共激活蛋白结合来刺激催乳素启动子。
Although the effects of the peroxisome proliferator-activated receptors (PPARs) have been studied primarily in adipocytes and liver, the wide distribution of these receptors suggests that they might also play a role in other cell types, We present evidence that PPAR activators stimulate the expression of the prolactin gene in pituitary GH4C1 cells. Transfection assays in non-pituitary HeLa cells showed that stimulation of the prolactin promoter by PPAR alpha requires the presence of the transcription factor GHF-1 (or Pit-1), Proximal promoter sequences confer responsiveness to PPAR alpha, and activation by this receptor is lost concomitantly with the response to GHF-1. Surprisingly, expression of the retinoid X receptor (RXR) abolishes stimulation by PPAR alpha, Furthermore, the promoter region that confers PPAR alpha responsiveness does not contain a PPAR response element. This suggests that the transcriptional effect of PPAR alpha might be mediated by protein-protein interactions rather than by binding of PPAR/RXR to the promoter. A direct interaction between PPAR alpha and GHF-1 was confirmed by in vitro binding studies, Expression of the coactivators SRC-1 and CREB-binding protein, which bind to PPAR, also enhanced the responsiveness of the prolactin promoter to PPAR alpha. Furthermore, CREB-binding protein also significantly increased activation by GHF-1, and both proteins associated in vitro, Thus, PPAR alpha, a receptor that normally acts as a ligand-dependent transcription factor by binding to specific DNA sequences in one context, can also stimulate the prolactin promoter by association with GHF-1 and coactivator proteins.