Abstract
AMPK is an AMP-activated protein kinase that plays an important role in regulating cellular energy homeostasis. Metabolic stress, such as heat shock and glucose starvation, causes an energy deficiency in the cell and leads to elevated levels of intracellular AMP. This results in the phosphorylation and activation of AMPK. LKB1, a tumor suppressor, has been identified as an upstream kinase of AMPK. We found that in response to treatment with 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), the LKB1 deficient cancer cell line, HeLa, exhibited AMPK-alpha phosphorylation. This indicates the existence of an LKB1-independent AMPK-alpha phosphorylation pathway. ATM is a protein that is deficient in the disease ataxia telangiectasia (A-T). We measured the activation of AMPK by AICAR in the normal mouse embryo fibroblast cell line, A29, and the mouse cell line lacking the ATM protein, A38. In A38 cells, the level of AICAR-induced AMPK-alpha phosphorylation was significantly lower than that found in A29 cells. Furthermore, phosphorylation of AMPK in HeLa and A29 cells was inhibited by an ATM specific inhibitor, KU-55933. Our results demonstrate that AICAR treatment could lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent manner. Thus, ATM may function as a potential AMPK kinase in response to AICAR treatment.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Aminoimidazole Carboxamide / analogs & derivatives*
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Aminoimidazole Carboxamide / metabolism
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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HeLa Cells / metabolism
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Humans
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Mice
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Mice, Knockout
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Multienzyme Complexes / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Serine-Threonine Kinases / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Ribonucleotides / metabolism*
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Signal Transduction
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Transfection
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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Tyrosine / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Multienzyme Complexes
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Ribonucleotides
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Tumor Suppressor Proteins
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Aminoimidazole Carboxamide
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Tyrosine
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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STK11 protein, human
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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AICA ribonucleotide