AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins

Leff, Todd

doi:10.1042/bst0310224

Cited by 149 publications

(104 citation statements)

References 30 publications

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“…Expression of these genes is regulated by the transcription factor HNF4α, which is a substrate of AMPK [27]. Phosphorylation of HNF4α by AMPK inhibits the formation of HNF4α homodimers and thus subsequently prevents HNF4α binding to DNA, while gene expression of HNF4α is not strongly regulated by AMPK activation [39]. Thus AMPK/HNF4α could represent an important axis of glucose-dependent gene regulation, not only for genes of glucose metabolism, but also for genes regulating beta cell growth, survival and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

et al. 2005

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Aims/hypothesis: Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. Materials and methods: We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. Results: In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high-and low-glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICARregulated mRNA expression of both receptors in INS-1E cells. Conclusions/interpretation: We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.

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Section: Discussionmentioning

confidence: 99%

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

et al. 2005

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“…Several mechanisms have been proposed by which AMPK could influence gene transcription. AMPK may act through Raf/Erk pathway (46), or may act via Raf-independent mechanisms, as AMPK␣2 has been localized to the nucleus (47) and directly regulates proteins involved in gene transcription (48). The contribution of these pathways remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase

Kim

Miller

Aja

et al. 2004

Journal of Biological Chemistry

268

243

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Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK ␣ subunit (pAMPK␣) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPK␣ levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPK␣ levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPK␣ and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.Despite significant advances in the understanding of appetite and satiety at molecular levels (1-3), practical therapies for weight loss remain elusive. We and others (4 -8) have demonstrated that C75, a synthetic fatty acid synthase (FAS) 1 inhibitor, caused profound weight loss and anorexia in lean, dietinduced obese (DIO) and genetically obese (ob/ob) mice. In addition to FAS inhibition, C75 also stimulates carnitine palmitoyltransferase-1 (CPT-1) activity, increasing fatty acid oxidation and ATP levels (8). Since enzymes of the fatty acid metabolic pathways are highly expressed in hypothalamic neurons that regulate feeding behavior (9), we hypothesize that C75-induced alterations in fatty acid metabolism may affect neuronal energy flux, which could signal a change in energy status, leading to changes in feeding behavior.AMPK (AMP-activated protein kinase) is activated by metabolic stresses such as nutrient starvation (10) and ischemiahypoxia (11) and by physiological processes such as vigorous exercise (12, 13). Specifically, increases in the AMP/ATP ratio, decreases in cellular pH, and increases in the creatine/phosphocreatine ratio are known to activate AMPK via allosteric activation of AMPK by AMP and by phosphorylation of AMPK by AMPKK (14 -19). Once activated, AMPK switches off ATPconsuming biosynthetic pathways such as fatty acid synthesis and switches on ATP-generating metabolic pathways such as fatty acid oxidation to preserve ATP levels (20, 21). The central roles of AMPK in both energy sensing and the control of fatty acid metabolism (16,22) and its r...

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“…In mammalian cells, AMPK has been proposed to regulate the expression of genes important for energy conservation at a time of low fuel availability (39). Although the direct effectors of this regulation have not been fully elucidated, a growing number of nuclear proteins, including transcription factors, have been identified as targets of phosphorylation by AMPK (73). In light of the results from this study, we propose that AMPK effects on importin ␣1, and possibly other importin ␣ proteins, further contribute to altering patterns of expressed genes by regulating the import of proteins that modulate gene expression at multiple levels.…”

Section: Fig 12mentioning

confidence: 99%

AMP-activated Protein Kinase-regulated Phosphorylation and Acetylation of Importin α1

Wang

Yang

Kawai

et al. 2004

Journal of Biological Chemistry

123

102

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Nuclear import of HuR, a shuttling RNA-binding protein, is associated with reduced stability of its target mRNAs. Increased function of the AMP-activated protein kinase (AMPK), an enzyme involved in responding to metabolic stress, was recently shown to reduce the cytoplasmic levels of HuR. Here, we provide evidence that importin ␣1, an adaptor protein involved in nuclear import, contributes to the nuclear import of HuR through two AMPK-modulated mechanisms. First, AMPK triggered the acetylation of importin ␣1 on Lys 22 , a process dependent on the acetylase activity of p300. Second, AMPK phosphorylated importin ␣1 on Ser 105 . Accordingly, expression of importin ␣1 proteins bearing K22R or S105A mutations failed to mediate the nuclear import of HuR in intact cells. Our results point to importin ␣1 as a critical downstream target of AMPK and key mediator of AMPK-triggered HuR nuclear import.

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AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins

Cited by 149 publications

References 30 publications

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase

AMP-activated Protein Kinase-regulated Phosphorylation and Acetylation of Importin α1

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