A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.
A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.
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DOI：
10.1038/oncsis.2017.51
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发表时间：
2017-06-26
期刊：
影响因子：
6.2
通讯作者：
Takahashi C
中科院分区：
文献类型：
--
作者：
Muranaka H;Hayashi A;Minami K;Kitajima S;Kohno S;Nishimoto Y;Nagatani N;Suzuki M;Kulathunga LAN;Sasaki N;Okada N;Matsuzaka T;Shimano H;Tada H;Takahashi C
在这里，通过结合脂质组学和转录组学分析，我们证明了小鼠胚胎成纤维细胞中Rb的消耗诱导了它们的脂质组成的显著改变。我们发现，Rb消耗诱导了溶磷脂酰丝氨酸、二酰基甘油（DAG）、脂肪酸（FA）、酰基肉碱、磷脂酰胆碱（PC）、花生四烯酰基乙醇胺的增加，以及磷脂酰甘油、单酰基甘油的减少，但每蛋白总脂质水平没有变化。对DAG、PC和磷脂酰丝氨酸的酰基链组成分析显示，饱和和单不饱和酰基链随碳链长度的增加而增加。一致地，我们观察到Rb缺失增加了相应碳链长度和碳-碳双键数量的脂肪酸水平，如肉豆蔻酸（14:0）、棕榈酸（16:0）、硬脂酸（18:0）和所有形式的FA 18:1。微阵列分析显示，Rb缺失诱导了与脂肪酸延伸和去饱和有关的酶的显著上调。其中，我们发现长链脂肪酸家族成员6的延伸（Elovl6）和硬脂酰辅酶a去饱和酶1 （Scd1）可能通过E2F和甾醇调节元件结合蛋白转录因子受到Rb最强烈的控制。Elovl6或Scd1的缺失显著抑制了rb缺陷肿瘤细胞的集落形成、球体形成和异种移植物肿瘤生长。通过补充由该酶产生的单不饱和脂肪酸，SCD1抑制剂对自我更新的抑制得以恢复。本研究提示Rb通过控制脂质组成在抑制肿瘤恶性进展中的新作用。
Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon–carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.
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DOI：
10.1016/j.bbrc.2008.01.075
发表时间：
2008-04-04
影响因子：
3.1
作者：
Kumadaki, Shin;Matsuzaka, Takashi;Shimano, Hitoshi
通讯作者：
Shimano, Hitoshi
影响因子：
4.3
作者：
Baenke F;Peck B;Miess H;Schulze A
通讯作者：
Schulze A
影响因子：
2.9
作者：
Feng, Yin-Hsun;Chen, Wei-Yu;Wu, Chao-Liang
通讯作者：
Wu, Chao-Liang
影响因子：
11.5
作者：
Clem, Brian F.;Chesney, Jason
通讯作者：
Chesney, Jason
DOI：
10.1016/j.ddtec.2015.03.002
发表时间：
2015-06-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Dehairs, Jonas;Derua, Rita;Swinnen, Johannes V
通讯作者：
Swinnen, Johannes V