Analysis of TAp73-Dependent Signaling via Omics Technologies
Analysis of TAp73-Dependent Signaling via Omics Technologies
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DOI：
10.1021/pr4005508
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Zolla, Lello
中科院分区：
文献类型：
--
作者：
D'Alessandro, Angelo;Marrocco, Cristina;Zolla, Lello
transactivation -精通（TA） p73是p53家族的一种转录因子，它调节多种生物过程，包括神经发生、分化、细胞凋亡和DNA损伤检查点反应。在本研究中，我们采用了多种组学方法，基于代谢组学、脂质组学和蛋白质组学的同时应用，以剖析p73激活的细胞内通路。作为细胞模型，我们使用了一个克隆人骨肉瘤SAOS-2细胞系，该细胞系允许以诱导方式表达TAp73 α。我们发现TAp73 α促进线粒体活性（代谢中间体的积累和与克雷布斯循环相关的蛋白质的上调），促进谷胱甘肽稳态，增加精氨酸-瓜氨酸- no代谢，改变嘌呤合成，促进戊糖磷酸途径积累NADPH以减少和生物合成目的。事实上，脂质代谢是朝着具有促凋亡潜能的长链脂肪酸的积累和氧化方向发展的。与此同时，TAp73 α的表达伴随着有丝分裂纺锤体组装检查点关键蛋白的去磷酸化。总之，这些结果证实了转录组学分析的现有证据，并表明TAp73 α在细胞代谢、细胞存活和细胞生长的调节中发挥作用。
Transactivation-proficient (TA) p73 is a transcription factor belonging to the p53 family, which regulates a variety of biological processes, including neurogenesis, differentiation, apoptosis, and DNA damage checkpoint response. In the present study, we adopted multiple Omics approaches, based upon the simultaneous application of metabolomics, lipidomics, and proteomics, in order to dissect the intracellular pathways activated by p73. As cellular model, we utilized a clone of the human osteosarcoma SAOS-2 cell line that allows the expression of TAp73 alpha in an inducible manner. We found that TAp73 alpha promoted mitochondrial activity (accumulation of metabolic intermediates and up-regulation of proteins related to the Krebs cycle), boosted glutathione homeostasis, increased arginine- citrulline-NO metabolism, altered purine synthesis, and promoted the pentose phosphate pathway toward NADPH accumulation for reducing and biosynthetic purposes. Indeed, lipid metabolism was driven toward the accumulation and oxidation of long-chain fatty acids with pro-apoptotic potential. In parallel, the expression of TAp73 alpha was accompanied by the dephosphorylation of key proteins of the mitotic spindle assembly checkpoint. In conclusion, the obtained results confirm existing evidence from transcriptomics analyses and suggest a role for TAp73 alpha in the regulation of cellular metabolism, cell survival, and cell growth.