CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation.,Molecular Cell

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CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation.
Molecular Cell ( IF 14.5 ) Pub Date : 2017-10-19 , DOI: 10.1016/j.molcel.2017.09.034
Isabel C Lopez-Mejia ₁ , Sylviane Lagarrigue ₂ , Albert Giralt ₃ , Laia Martinez-Carreres ₃ , Nadège Zanou ₄ , Pierre-Damien Denechaud ₁ , Judit Castillo-Armengol ₃ , Carine Chavey ₅ , Meritxell Orpinell ₂ , Brigitte Delacuisine ₁ , Anita Nasrallah ₃ , Caterina Collodet ₆ , Lianjun Zhang ₇ , Benoît Viollet ₈ , D Grahame Hardie ₉ , Lluis Fajas ₁

Affiliation

Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland; Institute of Sport Sciences, University of Lausanne, 1015 Lausanne, Switzerland.
IGMM, Université de Montpellier, UMR 5535 CNRS, 34293 Montpellier, France.
Nestlé Institute of Health Sciences SA, EPFL Innovation Park, 1015 Lausanne, Switzerland; École Polytechnique Fédérale de Lausanne, School of Life Sciences, 1015 Lausanne, Switzerland.
Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
Institut Cochin, INSERM U1016, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
School of Life Sciences, University of Dundee, Dundee, Scotland, UK.

The roles of CDK4 in the cell cycle have been extensively studied, but less is known about the mechanisms underlying the metabolic regulation by CDK4. Here, we report that CDK4 promotes anaerobic glycolysis and represses fatty acid oxidation in mouse embryonic fibroblasts (MEFs) by targeting the AMP-activated protein kinase (AMPK). We also show that fatty acid oxidation (FAO) is specifically induced by AMPK complexes containing the α2 subunit. Moreover, we report that CDK4 represses FAO through direct phosphorylation and inhibition of AMPKα2. The expression of non-phosphorylatable AMPKα2 mutants, or the use of a CDK4 inhibitor, increased FAO rates in MEFs and myotubes. In addition, Cdk4-/- mice have increased oxidative metabolism and exercise capacity. Inhibition of CDK4 mimicked these alterations in normal mice, but not when skeletal muscle was AMPK deficient. This novel mechanism explains how CDK4 promotes anabolism by blocking catabolic processes (FAO) that are activated by AMPK.

中文翻译：

CDK4 磷酸化 AMPKα2 以抑制其活性并抑制脂肪酸氧化。

CDK4 在细胞周期中的作用已被广泛研究，但对于 CDK4 代谢调节的潜在机制知之甚少。在此，我们报道 CDK4 通过靶向 AMP 激活蛋白激酶 (AMPK) 促进小鼠胚胎成纤维细胞 (MEF) 中的无氧糖酵解并抑制脂肪酸氧化。我们还表明，脂肪酸氧化 (FAO) 是由含有 α2 亚基的 AMPK 复合物特异性诱导的。此外，我们报告CDK4通过直接磷酸化和抑制AMPKα2来抑制FAO。非磷酸化 AMPKα2 突变体的表达或 CDK4 抑制剂的使用增加了 MEF 和肌管中的 FAO 率。此外，Cdk4-/-小鼠的氧化代谢和运动能力增强。 CDK4 的抑制模仿了正常小鼠的这些变化，但当骨骼肌 AMPK 缺陷时则不然。这种新颖的机制解释了 CDK4 如何通过阻断 AMPK 激活的分解代谢过程 (FAO) 来促进合成代谢。

更新日期：2017-10-19

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