Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.
Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.
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DOI：
10.1038/nature14587
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发表时间：
2015-08-20
期刊：
影响因子：
64.8
通讯作者：
Bardeesy, Nabeel
中科院分区：
文献类型：
--
作者：
Perera, RushikaM.;Stoykova, Svetlana;Nicolay, Brandon N.;Ross, Kenneth N.;Fitamant, Julien;Boukhali, Myriam;Lengrand, Justine;Deshpande, Vikram;Selig, Martin K.;Ferrone, Cristina R.;Settleman, Jeff;Stephanopoulos, Gregory;Dyson, Nicholas J.;Zoncu, Roberto;Ramaswamy, Sridhar;Haas, Wilhelm;Bardeesy, Nabeel
激活细胞应激反应途径以维持代谢稳态正在成为许多癌症中的关键生长和存活机制。胰腺导管腺癌（PDA）的发病机制需要高水平的自噬，一个保守的自我降解过程。然而，激活自噬和重新编程PDA细胞代谢的调节电路是未知的。我们现在表明，PDA中的自噬诱导作为更广泛的转录程序的一部分发生，该转录程序协调由MiT/TFE家族转录因子介导的溶酶体生物发生和功能的激活以及营养清除。在PDA细胞中，MiT/TFE蛋白- MITF、TFE 3和TFEB -与控制其细胞质保留的调节机制解耦。增加的核输入反过来又驱动了一个连贯的基因网络的表达，诱导高水平的溶酶体分解代谢功能的PDA的生长所必需的。无偏的整体代谢物分析表明，MiT/TFE依赖性自噬-溶酶体激活是维持细胞内氨基酸（AA）库所必需的。这些结果鉴定了MiT/TFE转录因子作为胰腺癌中代谢重编程的主调节因子，并证明了会聚于溶酶体的清除途径的激活是侵袭性恶性肿瘤的新标志。
Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. We now show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family transcription factors. In PDA cells, the MiT/TFE proteins – MITF, TFE3 and TFEB – are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular amino acid (AA) pools. These results identify the MiT/TFE transcription factors as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate activation of clearance pathways converging on the lysosome as a novel hallmark of aggressive malignancy.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
DOI：
10.1016/j.bbamcr.2010.10.014
发表时间：
2011-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Chook YM;Süel KE
通讯作者：
Süel KE
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
7.3
作者：
Martina JA;Diab HI;Lishu L;Jeong-A L;Patange S;Raben N;Puertollano R
通讯作者：
Puertollano R
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory