The AMP-activated protein kinase (AMPK) is a master regulator of metabolic homeostasis by sensing cellular energy status. AMPK is mainly activated via phosphorylation by LKB1 when cellular AMP/ADP levels are increased. However, how AMP/ADP brings about AMPK phosphorylation remains unclear. Here, we show that it is AMP, but not ADP, that drives AXIN to directly tether LKB1 to phosphorylate AMPK. The complex formation of AXIN-AMPK-LKB1 is greatly enhanced in glucose-starved or AICAR-treated cells and in cell-free systems supplemented with exogenous AMP. Depletion of AXIN abrogated starvation-induced AMPK-LKB1 colocalization. Importantly, adenovirus-based knockdown of AXIN in the mouse liver impaired AMPK activation and caused exacerbated fatty liver after starvation, underscoring an essential role of AXIN in AMPK activation. These findings demonstrate an initiating role of AMP and demonstrate that AXIN directly transmits AMP binding of AMPK to its activation by LKB1, uncovering the mechanistic route for AMP to elicit AMPK activation by LKB1.

IntroductionDeregulation of the proto-oncogene c-Myc (MYC) is considered one of a series of oncogenic events required for mammalian tumorigenesis. [1][2][3][4] MYC encodes a basic helix-loop-helix leucine zipper transcription factor that dimerizes with its partner, Max, and regulates multiple cellular functions including cell cycle, cell growth, differentiation, apoptosis, metabolism, and angiogenesis via transcription of downstream target genes. 2 The Myc/Max dimer can also repress transcription of another set of target genes through a less well-understood mechanism. 5,6 The c-Myc proto-oncogene is involved in transformation and cell proliferation in part via activation of the cyclin D2 promoter, 7 but also induces programmed cell death, mediated by nuclear respiratory factor 1 (NRF-1) 8 and the Arf-p53 pathway. 9,10 Forced expression of Myc in primary cells is generally thought to induce growth arrest or apoptosis. 11,12 The oncogenic function of c-Myc has been best studied in the E-Myc transgenic mouse, in which c-Myc expression is targeted to the lymphoid compartment by the immunoglobulin heavy chain gene promoter and enhancer. 13 In E-Myc mice, expression of Myc is not sufficient to cause leukemia. A latency period of 4 to 6 months is required for the accumulation of cooperating mutations before lymphoma can develop. 14 The majority of the E-Myc tumors harbor mutations in the now canonical Arf-Mdm2-p53 pathway. 14,15 Although the p53 pathway controls many functions including cell cycle, DNA damage response, and apoptosis, Bcl-2, or dominant-negative caspase 9 also cooperate with Myc, and alleviate the pressure to inactivate p53 during lymphomagenesis. 15 Therefore, of the many functions of the Arf-Mdm2-p53 pathway, it is the ability to mediate apoptosis that is targeted by cooperating mutations in Myc-induced lymphomagenesis.MYC dysregulation, via a variety of mechanisms, has also been associated with myeloid leukemias. 16 Double minute chromosomes in patients with acute myeloid leukemia (AML) contain MYC amplifications. 17,18 c-Myc expression is apparently required for the oncogenic effects of the Philadelphia chromosome product, BCL-ABL, 19 and overexpression of c-Myc also complements the transformation defects of BCR-ABL mutants. 20 A recent study showed that many important oncogenes in myeloid leukemogenesis including AML1-ETO, PML-RARA, and PLZF-RARA induce leukemogenesis by activating c-Myc, 21 suggesting c-Myc is a downstream target of these oncogenes. Lastly, c-Myc is upregulated by activating mutations in the gene encoding the FLT3 receptor tyrosine kinase, found in nearly one-third of all patients with AML. 22,23 There is a lack of useful animal models for studying the role of Myc in myeloid leukemia. AML infrequently develops in ESRMyc mice, in which a heterologous promoter inducibly drives Myc expression in bone marrow cells; however, most of these animals develop T-cell lymphomas, 24 making it a cumbersome system to Using the murine stem cell virus (MSCV) system to broadly express Myc in primar...

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