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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish
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The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish

机译：丝氨酸-苏氨酸激酶LKB1对于斑马鱼在高能胁迫下的生存至关重要

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摘要

Mutations in the serine-threonine kinase (LKB1) lead to a gastrointestinal hamartomatous polyposis disorder with increased predisposition to cancer (Peutz-Jeghers syndrome). LKB1 has many targets, including the AMP-activated protein kinase (AMPK) that is phosphorylated under low-energy conditions. AMPK phosphor-ylation in turn, affects several processes, including inhibition of the target of rapamycin (TOR) pathway, and leads to proliferation inhibition. To gain insight into how LKB1 mediates its effects during development, we generated zebrafish mutants in the single LKB1 ortholog. We show that in zebrafish Ikb1 is dispensable for embryonic survival but becomes essential under conditions of energetic stress. After yolk absorption, Ikb1 mutants rapidly exhaust their energy resources and die prematurely from starvation. Notably, intestinal epithelial cells were polarized properly in the Ikb1 mutants. We show that attenuation of metabolic rate in Ikb1 mutants, either by application of the TOR inhibitor rapamycin or by crossing with von Hippel-Lindau (vhl) mutant fish (in which constitutive hypoxia signaling results in reduced metabolic rate), suppresses key aspects of the Ikb1 phenotype. Thus, we demonstrate a critical role for LKB1 in regulating energy homeostasis at the whole-organism level in a vertebrate. Zebrafish models of Lkb1 inactivation could provide a platform for chemical genetic screens to identify compounds that target accelerated metabolism, a key feature of tumor cells.
机译：丝氨酸-苏氨酸激酶（LKB1）中的突变会导致胃肠道错构瘤性息肉病，并易患癌症（Peutz-Jeghers综合征）。 LKB1具有许多靶标，包括在低能条件下被磷酸化的AMP激活蛋白激酶（AMPK）。 AMPK磷酸化反过来会影响多个过程，包括抑制雷帕霉素（TOR）途径的靶标，并导致增殖抑制。为了深入了解LKB1在发育过程中如何介导其作用，我们在单个LKB1直系同源物中生成了斑马鱼突变体。我们显示在斑马鱼中，Ikb1对于胚胎存活是必不可少的，但在精力充沛的条件下变得必不可少。卵黄吸收后，Ikb1突变体迅速耗尽其能量，并因饥饿而过早死亡。值得注意的是，肠上皮细胞在Ikb1突变体中被正确极化。我们显示，通过应用TOR抑制剂雷帕霉素或与von Hippel-Lindau（vhl）突变鱼杂交（其中组成性缺氧信号导致代谢率降低），Ikb1突变体的代谢速率降低，抑制了关键的方面。 Ikb1表型。因此，我们证明了LKB1在调节脊椎动物体内全生物水平能量稳态中的关键作用。 Lkb1失活的斑马鱼模型可以为化学遗传筛选提供平台，以识别靶向加速代谢的化合物，这是肿瘤细胞的关键特征。

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    Yme U. van der Velden; Liqin Wang; John Zevenhoven; Ellen van Rooijen; Maarten van Lohuizen; Rachel H. Giles; Hans Clevers; Anna-Pavlina G. Haramis;

  • 作者单位

    Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

    Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

    Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

    Hubrecht Institute, 3584 CT, Utrecht, The Netherlands Departments of Medical Oncology, University Medical Center, 3584 CX, Utrecht, The Netherlands;

    Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

    Departments of Medical Oncology, University Medical Center, 3584 CX, Utrecht, The Netherlands Departments of Nephrology, University Medical Center, 3584 CX, Utrecht, The Netherlands;

    Hubrecht Institute, 3584 CT, Utrecht, The Netherlands;

    Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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