p63 regulates glutaminase 2 expression
p63 regulates glutaminase 2 expression
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DOI：
10.4161/cc.24478
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发表时间：
2013-05-01
期刊：
影响因子：
4.3
通讯作者：
Peschiaroli, Angelo
中科院分区：
文献类型：
--
作者：
Giacobbe, Arianna;Bongiorno-Borbone, Lucilla;Peschiaroli, Angelo
转录因子p63对许多生物学过程至关重要，包括表皮组织的发育和维持以及肿瘤发生。在这里，我们报告了TAp 63亚型通过诱导原代细胞和肿瘤细胞系中的线粒体谷氨酰胺酶2（GLS 2）基因来调节细胞代谢。通过ChIP分析和荧光素酶分析，我们证实了TAp 63直接结合到GLS 2启动子区域内的p53/p63共有DNA结合序列。鉴于p63在表皮分化中的关键作用，我们研究了在此过程中GLS 2表达的调节。在原代人角质形成细胞的体外分化过程中，GLS 2和TAp 63表达增加，GLS 2的缺失在分子和细胞水平上抑制皮肤分化。我们发现，GLS 2和TAp 63的表达是伴随诱导暴露于氧化应激的癌细胞。siRNA介导的GLS 2耗竭使细胞对ROS诱导的细胞凋亡敏感，这表明TAp 63/GLS 2轴在p53不存在的情况下作为细胞抗氧化途径在功能上是重要的。因此，我们发现GLS 2在结肠腺癌中上调。总之，我们的研究结果表明，GLS 2是一个真正的TAp 63靶基因，并且GLS 2的TAp 63依赖性调节对于生理和病理过程都很重要。
The transcription factor p63 is critical for many biological processes, including development and maintenance of epidermal tissues and tumorigenesis. Here, we report that the TAp63 isoforms regulate cell metabolism through the induction of the mitochondrial glutaminase 2 (GLS2) gene both in primary cells and tumor cell lines. By ChIP analysis and luciferase assay, we confirmed that TAp63 binds directly to the p53/p63 consensus DNA binding sequence within the GLS2 promoter region. Given the critical role of p63 in epidermal differentiation, we have investigated the regulation of GLS2 expression during this process. GLS2 and TAp63 expression increases during the in vitro differentiation of primary human keratinocytes, and depletion of GLS2 inhibits skin differentiation both at molecular and cellular levels. We found that GLS2 and TAp63 expression are concomitantly induced in cancer cells exposed to oxidative stresses. siRNA-mediated depletion of GLS2 sensitizes cells to ROS-induced apoptosis, suggesting that the TAp63/GLS2 axis can be functionally important as a cellular antioxidant pathway in the absence of p53. Accordingly, we found that GLS2 is upregulated in colon adenocarcinoma. Altogether, our findings demonstrate that GLS2 is a bona fide TAp63 target gene, and that the TAp63-dependent regulation of GLS2 is important for both physiological and pathological processes.