CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation

López-Mejía, Isabel C.; Lagarrigue, Sandrine; Giralt, Albert; Martínez-Carreres, Laia; Zanou, Nadège; Denechaud, Pierre-Damien; Castillo-Armengol, Judit; Chavey, Carine; Orpinell, Meritxell; Delacuisine, Brigitte; Nasrallah, Anita; Collodet, Caterina; Zhang, Lianjun; Viollet, Benoı̂t; Hardie, D. Grahame; Fajas, Lluís

doi:10.1016/j.molcel.2017.09.034

Cited by 63 publications

(52 citation statements)

References 70 publications

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“…Altogether, the general function of CDK4 is to redirect energy availability to biosynthetic processes, rather than to energy-consuming processes like heat generation and dissipation, resulting for example in a decrease in BAT activation. This is consistent with the known role of CDK4 in controlling several biosynthetic pathways (Lagarrigue et al, 2016;Lopez-Mejia et al, 2017).…”

supporting

confidence: 90%

“…Growing evidence demonstrates that a regulatory crosstalk exists between metabolic pathways and regulators of cell cycle progression. Our laboratory and others have demonstrated that CDK4 is one of such "metabolic" cell cycle regulators (Blanchet et al, 2011;Denechaud et al, 2016;Lagarrigue et al, 2016;Lopez-Mejia et al, 2017). CDK4 participates in the G1/S transition phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 96%

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Hypothalamic CDK 4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues

et al. 2020

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This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4−/− mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell‐autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron‐specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4−/− mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain.

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supporting

confidence: 90%

Section: Introductionmentioning

confidence: 96%

Hypothalamic CDK 4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues

et al. 2020

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“…Oncogene Non-small cell lung cancer [7,8] , cervical cancer [7] , melanoma [7,9] , liposarcoma [10] and others Cell-cycle check-point regulation, metabolism (anaerobic glycolysis) [11] 11 TLK2 Amplificatio n oncogene Oncogene Breast cancer [12,13] , glioblastoma [14] Genomic instability [12] , src signalling pathway [14] 12 IL6 Amplificatio n oncogene Oncogene Liver cancer [15] , breast cancer [16] , head and neck squamous cell carcinoma [17] , prostate cancer [15,18] STAT3 activation, insulin-growth factor signaling, inflammation 13 HAS2 Amplificatio n oncogene…”

mentioning

confidence: 99%

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Han

Goralski

Gaskill

et al. 2017

Science

525

542

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Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

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“…In doing so, AMPK promotes bioenergetics processes such as glycolysis, autophagy, and FAO, while concomitantly inhibiting energetically costly anabolic processes such as FA synthesis [157] . Importantly, palbociclib was recently shown to induce activation of AMPK [159] and CDK4 has been shown to suppress FAO by directly antagonizing AMPKa2 [160] . Therefore, AMPK activation may be a valuable therapeutic target to antagonize mTOR-mediated lipid metabolic reprogramming.…”

Section: Targeting Lipid Metabolic Rewiring In Drug Resistant Cancer mentioning

confidence: 99%

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

Feng¹,

Kurokawa²

2019

CDR

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Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.

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CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation

Cited by 63 publications

References 70 publications

Hypothalamic CDK 4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues

Hypothalamic CDK 4 regulates thermogenesis by modulating sympathetic innervation of adipose tissues

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

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