基于 LC-Orbitrap HRMS 的蛋白质组学揭示了与果蝇 RasV12 诱导的胶质母细胞瘤 (GBM) 相关的新型线粒体动力学调控蛋白。

IF 3.8 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Journal of Proteome Research Pub Date : 2024-11-01 Epub Date: 2024-10-16 DOI:10.1021/acs.jproteome.4c00502
Pradeep Kumar, Rohit Kumar, Prabhat Kumar, Sunaina Kushwaha, Sandhya Kumari, Neha Yadav, Saripella Srikrishna
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引用次数: 0

摘要

多形性胶质母细胞瘤(GBM)是成人中最常见的侵袭性脑肿瘤,预后不良,平均存活期为 14-15 个月。为了全面了解其蛋白质组,并确定新的治疗靶点,本研究主要关注 RasV12 诱导的 GBM 的差异丰度蛋白(DAPs)。RasV12 是一种组成型活性 Ras 突变体,通过持续激活信号通路导致肿瘤失控生长,对肿瘤的进展至关重要。本研究利用转基因果蝇模型,使用 repo-GAL4 驱动系进行 RasV12 过表达,特别是在神经胶质细胞中研究 GBM。基于高分辨率质谱(HRMS)的蛋白质组学分析发现了三种特异于线粒体的新型 DAPs。通过 HRMS 鉴定出的这些 DAPs(可能是马来酰乙酰乙酸异构酶 2 (Q9VHD2)、双功能亚甲基四氢叶酸脱氢酶 (Q04448) 和谷氨酰胺合成酶 1 (P20477))通过 qRT-PCR 得到了进一步验证。蛋白-蛋白相互作用分析表明,RasV12 与 DAPs 之间存在相互作用,并与 Drp1、Marf、Parkin 和 HtrA2 等线粒体动力学调控因子存在功能联系。值得注意的是,在 GBM 进展过程中观察到 Q9VHD2、P20477 和 Q04448 的表达发生了改变,这为线粒体动态调节因子参与 RasV12 诱导的 GBM 病理生理学提供了新的见解。
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LC-Orbitrap HRMS-Based Proteomics Reveals Novel Mitochondrial Dynamics Regulatory Proteins Associated with RasV12-Induced Glioblastoma (GBM) of Drosophila.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor found in adult humans with a poor prognosis and average survival of 14-15 months. In order to have a comprehensive understanding of proteome and identify novel therapeutic targets, this study focused mainly on the differentially abundant proteins (DAPs) of RasV12-induced GBM. RasV12 is a constitutively active Ras mutant form essential for tumor progression by continuously activating signaling pathways leading to uncontrolled tumor growth. This study used a transgenic Drosophila model with RasV12 overexpression using the repo-GAL4 driver line, specifically in glial cells, to study GBM. The high-resolution mass spectrometry (HRMS)-based proteomic analysis of the GBM larval central nervous system identified three novel DAPs specific to mitochondria. These DAPs, probable maleylacetoacetate isomerase 2 (Q9VHD2), bifunctional methylene tetrahydrofolate dehydrogenase (Q04448), and glutamine synthetase1 (P20477), identified through HRMS were further validated by qRT-PCR. The protein-protein interaction analysis revealed interactions between RasV12 and DAPs, with functional links to mitochondrial dynamics regulators such as Drp1, Marf, Parkin, and HtrA2. Notably, altered expressions of Q9VHD2, P20477, and Q04448 were observed during GBM progression, which offers new insights into the involvement of mitochondrial dynamic regulators in RasV12-induced GBM pathophysiology.

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来源期刊
Journal of Proteome Research
Journal of Proteome Research 生物-生化研究方法
CiteScore
9.00
自引率
4.50%
发文量
251
审稿时长
3 months
期刊介绍: Journal of Proteome Research publishes content encompassing all aspects of global protein analysis and function, including the dynamic aspects of genomics, spatio-temporal proteomics, metabonomics and metabolomics, clinical and agricultural proteomics, as well as advances in methodology including bioinformatics. The theme and emphasis is on a multidisciplinary approach to the life sciences through the synergy between the different types of "omics".
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