Peroxisome proliferator-activated receptor γ (PPARγ) mediates a Ski oncogene-induced shift from glycolysis to oxidative energy metabolism.
Peroxisome proliferator-activated receptor γ (PPARγ) mediates a Ski oncogene-induced shift from glycolysis to oxidative energy metabolism.
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过氧化物酶体增殖物激活受体γ (PPARγ) 介导Ski 癌基因诱导的从糖酵解到氧化能量代谢的转变。
DOI：
10.1074/jbc.m111.292029
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Stavnezer,Ed
中科院分区：
文献类型：
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作者：
Ye,Fang;Lemieux,Hélène;Hoppel,CharlesL;Hanson,RichardW;Hakimi,Parvin;Croniger,ColleenM;Puchowicz,Michelle;Anderson,VernonE;Fujioka,Hisashi;Stavnezer,Ed
Skioncogene的过表达诱导鸡胚成纤维细胞（CEFs）的致癌转化。然而，与大多数其他癌基因转化的细胞不同，Ski转化的CEF（Ski-CEF）不显示经典的瓦尔堡效应。相反，Ski转化降低了CEFs中的乳酸产生和葡萄糖利用。与CEFs相比，Ski-CEFs的TCA循环活性、β-氧化脂肪酸催化活性、谷氨酸氧化活性、耗氧量以及线粒体数量和质量均有所增加。有趣的是，在Ski-CEFs中，调节脂肪形成和脂质代谢的关键转录因子PPARγ的表达在mRNA和蛋白水平上都显著升高。因此，参与脂质摄取、转运和氧化的PPARγ靶基因也被Ski显著上调。通过RNA干扰敲低Ski-CEFs中的PPAR γ，逆转了这些PPARγ靶基因的高表达，以及氧化代谢的转变和线粒体生物合成的增加。此外，我们发现Ski与PPARγ共免疫沉淀并共激活PPARγ驱动的转录。
Overexpression of theSkioncogene induces oncogenic transformation of chicken embryo fibroblasts (CEFs). However, unlike most other oncogene-transformed cells, Ski-transformed CEFs (Ski-CEFs) do not display the classical Warburg effect. On the contrary, Ski transformation reduced lactate production and glucose utilization in CEFs. Compared with CEFs, Ski-CEFs exhibited enhanced TCA cycle activity, fatty acid catabolism through β-oxidation, glutamate oxidation, oxygen consumption, as well as increased numbers and mass of mitochondria. Interestingly, expression of PPARγ, a key transcription factor that regulates adipogenesis and lipid metabolism, was dramatically elevated at both the mRNA and protein levels in Ski-CEFs. Accordingly, PPARγ target genes that are involved in lipid uptake, transport, and oxidation were also markedly up-regulated by Ski. Knocking downPPARγ in Ski-CEFs by RNA interference reversed the elevated expression of these PPARγ target genes, as well as the shift to oxidative metabolism and the increased mitochondrial biogenesis. Moreover, we found that Ski co-immunoprecipitates with PPARγ and co-activates PPARγ-driven transcription.