Induction of PPARβ and prostacyclin (PGI2) synthesis by Raf signaling:: failure of PGI2 to activate PPARβ
Induction of PPARβ and prostacyclin (PGI2) synthesis by Raf signaling:: failure of PGI2 to activate PPARβ
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DOI：
10.1111/j.1742-4658.2005.05055.x
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发表时间：
2006-01-01
期刊：
影响因子：
5.4
通讯作者：
Müller, R
中科院分区：
文献类型：
--
作者：
Fauti, T;Müller-Brüsselbach, S;Müller, R
核受体过氧化物酶体增殖物激活受体β（PPAR β）在肿瘤发生中的作用已被许多观察所证实，但其确切作用仍然难以捉摸。前列腺素I-2（PGI（2），前列环素）是一种主要的花生四烯酸（AA）衍生的环氧合酶（考克斯）产物，被认为是一种过氧化物酶体增殖物激活受体β激动剂。在这里，我们发现4-羟基他莫昔芬（4-OHT）介导的C-Raf-雌激素受体融合蛋白的激活导致了PPAR β和考克斯-2基因的诱导，伴随着PGI（2）合成的显著增加。然而，令人惊讶的是，4-OHT不能激活PPAR β转录活性，表明PGI（2）不足以激活PPAR β。与该结论一致，异位考克斯-2和PGI（2）合酶（PGIS）的过表达导致大量PGI（2）合成，但不激活PPAR β的转录活性。相反，抑制PGIS可以阻断PGI（2）的合成，但不影响AA介导的PPAR β激活。我们用四种不同的细胞类型和不同的实验策略获得的数据并不支持PGI（2）在调节PPAR β中起重要作用的流行观点。
A role for the nuclear receptor peroxisome proliferator-activated receptor-beta (PPAR beta) in oncogenesis has been suggested by a number of observations but its precise role remains elusive. Prostaglandin I-2 (PGI(2), prostacyclin), a major arachidonic acid (AA) derived cyclooxygenase (Cox) product, has been proposed as a PPAR beta agonist. Here, we show that the 4-hydroxytamoxifen (4-OHT) mediated activation of a C-Raf-estrogen receptor fusion protein leads to the induction of both the PPAR beta and Cox-2 genes, concomitant with a dramatic increase in PGI(2) synthesis. Surprisingly, however, 4-OHT failed to activate PPAR beta transcriptional activity, indicating that PGI(2) is insufficient for PPAR beta activation. In agreement with this conclusion, the overexpression of ectopic Cox-2 and PGI(2) synthase (PGIS) resulted in massive PGI(2) synthesis but did not activate the transcriptional activity of PPAR beta. Conversely, inhibition of PGIS blocked PGI(2) synthesis but did not affect the AA mediated activation of PPAR beta. Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI(2) plays a significant role in the regulation of PPAR beta.