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Lee, Yoonjin

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Yoonjin

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Lee, Yoonjin

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Author's Publications: search.filters.isAuthorOfPublication.96409575-b37e-48ce-8392-3c5759750cb4

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    A Chemical Approach Identifies CDK4 as a Regulatory Component of Glucose Metabolism
    (2014-06-06) Lee, Yoonjin; Puigserver, Pere Puigserver; King, Randall; Saghatelian, Alan
    Mammals have to adapt quickly to the changes of nutrition availability. The liver is the central organ that coordinates the responses to food deprivation upon fasting and nutrient overload during feeding. In liver, hormonal and nutrient pathways converge into the regulation of transcriptional programs that are involved in maintaining energy homeostasis. When these fine-tuned regulations in liver are altered due to constant surplus of nutrients or insufficient hormonal actions, multiple metabolic diseases including type II diabetes can occur, followed by severe complications. As a part of those regulatory programs, PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha) links hormonal signaling to the expression of glucose and lipid metabolic genes. Its transcriptional co-activator activity is tightly controlled via post-translational modification; GCN5 (histone acetyltransferase KAT2A) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas Sirt1 deacetylates and activates PGC-1alpha. Herein, cyclin D1-CDK4 (cyclin-dependent kinase 4) kinase is identified as a new regulator of glucose metabolism in liver that modulates PGC-1alpha's transcriptional activity. Through a cell-based high throughput chemical screen, a CDK4 inhibitor was discovered to potently decrease PGC-1alpha acetylation. Cyclin D1-CDK4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1alpha activity on hepatic gluconeogenic genes. Feeding activates cyclin D1-CDK4 kinase in liver, which, in turn, suppresses glucose production independently of cell cycle progression. As part of the feeding response, insulin/GSK3beta (glycogen synthase kinase 3beta) signaling stabilizes cyclin D1 protein via sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 mRNA transcripts. Loss of hepatic cyclin D1 in mice leads to mild diabetic phenotypes. In diabetic models, cyclin D1-CDK4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycemia. Thus, these findings show that hormonal and nutrient pathways utilize components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell cycle progression.
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    Cyclin D1-CDK4 Controls Glucose Metabolism Independently of Cell Cycle Progression
    (2014) Lee, Yoonjin; Dominy, John E.; Choi, Yoon Jong; Jurczak, Michael; Tolliday, Nicola; Camporez, Joao Paulo; Chim, Helen; Lim, Ji-Hong; Ruan, Hai-Bin; Yang, Xiaoyong; Vazquez, Francisca; Sicinski, Piotr; Shulman, Gerald I.; Puigserver, Pere
    Insulin constitutes a major evolutionarily conserved hormonal axis for maintaining glucose homeostasis1-3; dysregulation of this axis causes diabetes2,4. PGC-1α links insulin signaling to the expression of glucose and lipid metabolic genes5-7. GCN5 acetylates PGC-1α and suppresses its transcriptional activity, whereas SIRT1 deacetylates and activates PGC-1α8,9. Although insulin is a mitogenic signal in proliferative cells10,11, whether components of the cell cycle machinery contribute to insulin’s metabolic action is poorly understood. Herein, we report that insulin activates cyclin D1-CDK4, which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high throughput chemical screen, we identified a CDK4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK3β signaling induces cyclin D1 protein stability via sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 mRNA transcripts. Activated cyclin D1-CDK4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycemia. In diabetic models, cyclin D1-CDK4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.