PIM1通過(guò)抑制重編程誘導(dǎo)的鐵下垂和細(xì)胞周期阻滯促進(jìn)肝臟轉(zhuǎn)化

2022年9月6日，中國(guó)醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院生物醫(yī)學(xué)工程研究所，上海工業(yè)大學(xué)生命科學(xué)與技術(shù)學(xué)院，分子生物物理教育部重點(diǎn)實(shí)驗(yàn)室，湖北省生物信息學(xué)與分子成像重點(diǎn)實(shí)驗(yàn)室，人工智能生物學(xué)中心，華中生命科學(xué)與技術(shù)學(xué)院人工智能研究所，武漢科技大學(xué)，復(fù)旦大學(xué)眼耳鼻喉醫(yī)院耳鼻喉科，醫(yī)學(xué)神經(jīng)生物學(xué)與生物醫(yī)學(xué)研究所國(guó)家重點(diǎn)實(shí)驗(yàn)室，國(guó)家衛(wèi)生健康委聽(tīng)力醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，南京大學(xué)人工智能生物醫(yī)學(xué)研究所，香港轉(zhuǎn)化干細(xì)胞生物學(xué)中心有限公司（Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.

School of Life Scienceand Technology, ShanghaiTech University, Shanghai 201210, China.

MOE Key Laboratory of Molecular Biophysics, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Center for Artificial Intelligence Biology, Institute of Artificial Intelligence, College of Life Science and Technology, Huazhong

University of Science and Technology, Wuhan 430074 Hubei, China.

ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and Institutes of Biomedical Sciences, Fudan University, Shanghai 200031, China.

NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.

Nanjing University Institute of Artificial Intelligence Biomedicine, Nanjing, Jiangsu 210031, China.

Present address: Centre for Translational Stem Cell Biology Limited, Hong Kong 999077, China.） Yu Xue & Pengyu Huang研究團(tuán)隊(duì)，在《nature communications 》發(fā)表了論文，標(biāo)題為：“PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest”“PIM1通過(guò)抑制重編程誘導(dǎo)的鐵下垂和細(xì)胞周期阻滯促進(jìn)肝臟轉(zhuǎn)化”

Abstract

Protein kinase-mediated phosphorylation plays a critical role in many biological processes.   However, the identification of key regulatory kinases is still a great challenge.   Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data.   Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis.   We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two processes.   Further experiments reveal that a serine/threonine kinase, PIM1, promotes hepatic conversion and protects human dermal fibroblasts from reprogramming-induced ferroptosis and cell cycle arrest.   This study not only reveals new regulatory kinases, but also provides a helpful method that might be extended to predict central kinases involved in other biological processes.

摘要

蛋白激酶介導(dǎo)的磷酸化在許多生物過(guò)程中起著關(guān)鍵作用。然而，關(guān)鍵調(diào)控激酶的鑒定仍然是一個(gè)巨大的挑戰(zhàn)。在這里，我們開(kāi)發(fā)了一種基于反式組學(xué)的方法，中央激酶推斷，通過(guò)整合定量轉(zhuǎn)錄組學(xué)和磷酸化蛋白質(zhì)組學(xué)數(shù)據(jù)來(lái)預(yù)測(cè)潛在的關(guān)鍵激酶。使用已知的與抗癌藥物耐藥相關(guān)的激酶，我們的方法的曲線下面積表示的準(zhǔn)確度比激酶底物富集分析高出5.2%至29.5%。我們進(jìn)一步利用這種方法分析了肝細(xì)胞成熟和人類(lèi)真皮成纖維細(xì)胞肝臟重編程的反組學(xué)數(shù)據(jù)，發(fā)現(xiàn)了5種激酶在這兩個(gè)過(guò)程中起調(diào)節(jié)作用。進(jìn)一步的實(shí)驗(yàn)表明，絲氨酸/蘇氨酸激酶PIM1促進(jìn)肝臟轉(zhuǎn)化，并保護(hù)人類(lèi)真皮成纖維細(xì)胞免受重編程誘導(dǎo)的鐵凋亡和細(xì)胞周期阻滯。這項(xiàng)研究不僅揭示了新的調(diào)控激酶，而且提供了一種有用的方法，可以擴(kuò)展到預(yù)測(cè)參與其他生物過(guò)程的中樞激酶。

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