Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation.
Transcriptomic analysis of mitochondrial TFAM depletion changing cell morphology and proliferation.
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DOI：
10.1038/s41598-017-18064-9
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发表时间：
2017-12-19
影响因子：
4.6
通讯作者：
Kang C
中科院分区：
文献类型：
--
作者：
Lee WR;Na H;Lee SW;Lim WJ;Kim N;Lee JE;Kang C
人线粒体转录因子A（TFAM）与促进肿瘤生长和侵袭有关。TFAM激活线粒体DNA（mtDNA）转录，并通过线粒体逆行信号影响核基因表达。在这项研究中，我们研究了TFAM缺失对MKN 45胃癌细胞形态和转录组的影响。TFAM敲除后12 h，形态学改变变得可见：生长停滞的多边形细胞与椭圆形细胞的比例增加，在24 h达到半最大值，在36 h接近最大值。TFAM敲低在24 h和48 h时上调了4个基因，下调了6个基因超过3倍。其中，CFAP 65（纤毛和鞭毛相关蛋白65）或PCK 1（细胞质磷酸烯醇式丙酮酸羧激酶）的敲低挽救了TFAM耗竭对细胞形态和增殖的影响。发现PCK 1在钙介导的逆行信号传导中作用于CFAP 65的下游。2′，3 ′-双脱氧胞苷去除线粒体DNA可诱导CFAP 65和PCK 1表达，抑制细胞增殖，而氧化磷酸化阻断或线粒体膜电位去极化则不能。因此，TFAM-mtDNA-钙-CFAP 65-PCK 1轴参与线粒体逆行信号传导，影响肿瘤细胞分化和增殖。
Human mitochondrial transcription factor A (TFAM) has been implicated in promoting tumor growth and invasion. TFAM activates mitochondrial DNA (mtDNA) transcription, and affects nuclear gene expression through mitochondrial retrograde signaling. In this study, we investigated the effects of TFAM depletion on the morphology and transcriptome of MKN45 gastric cancer cells. Morphology alteration became visible at 12 h after TFAM knockdown: the proportion of growth-arrested polygonal cells versus oval-shaped cells increased, reaching a half-maximum at 24 h and a near-maximum at 36 h. TFAM knockdown upregulated four genes and downregulated six genes by more than threefold at 24 h and similarly at 48 h. Among them, the knockdown of CFAP65 (cilia and flagella associated protein 65) or PCK1 (cytoplasmic phosphoenolpyruvate carboxykinase) rescued the effects of TFAM depletion on cell morphology and proliferation. PCK1 was found to act downstream of CFAP65 in calcium-mediated retrograde signaling. Furthermore, mtDNA depletion by 2′,3′-dideoxycytidine was sufficient for induction of CFAP65 and PCK1 expression and inhibition of cell proliferation, but oxidative phosphorylation blockade or mitochondrial membrane potential depolarization was not. Thus, the TFAM–mtDNA–calcium–CFAP65–PCK1 axis participates in mitochondrial retrograde signaling, affecting tumor cell differentiation and proliferation.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
11.4
作者：
Biswas, G;Adebanjo, OA;Avadhani, NG
通讯作者：
Avadhani, NG
影响因子：
2
作者：
Kimura, Tomoko;Kitada, Shohei;Yamada, Sohsuke
通讯作者：
Yamada, Sohsuke
影响因子：
3.5
作者：
Ekstrand, MI;Falkenberg, M;Larsson, NG
通讯作者：
Larsson, NG
影响因子：
--
作者：
De Luca A;Fiorillo M;Peiris-Pagès M;Ozsvari B;Smith DL;Sanchez-Alvarez R;Martinez-Outschoorn UE;Cappello AR;Pezzi V;Lisanti MP;Sotgia F
通讯作者：
Sotgia F