The nuclear protein Artemis promotes AMPK activation by stabilizing the LKB1-AMPK complex.

AMP-activated protein kinase (AMPK) is a hetero-trimeric Ser/Thr kinase composed of a catalytic α subunit and regulatory ß and γ subunits; it functions as an energy sensor that controls cellular energy homeostasis. In response to an increased cellular AMP/ATP ratio, AMPK is activated by phosphorylation at Thr172 in the α-subunit by upstream AMPK kinases (AMPKKs), including tumor suppressor liver kinase B1 (LKB1). To elucidate more precise molecular mechanisms of AMPK activation, we performed yeast two-hybrid screening and isolated the complementary DNA (cDNA) encoding the nuclear protein Artemis/DNA cross-link repair 1C (DCLRE1C) as an AMPKα2-binding protein. Artemis was found to co-immunoprecipitate with AMPKα2, and the co-localization of Artemis with AMPKα2 in the nucleus was confirmed by immunofluorescence staining in U2OS cells. Moreover, over-expression of Artemis enhanced the phosphorylation of AMPKα2 and the AMPK substrate acetyl-CoA carboxylase (ACC). Conversely, RNAi-mediated knockdown of Artemis reduced AMPK and ACC phosphorylation. In addition, Artemis markedly increased the physical association between AMPKα2 and LKB1. Taken together, these results suggest that Artemis functions as a positive regulator of AMPK signaling by stabilizing the LKB1-AMPK complex.

The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma.

BACKGROUND: Prediction and prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) recurrence is an important clinical issue. We investigated whether HBV DNA level and antiviral therapy are associated with HCC recurrence. METHODS: This retrospective study involved 103 patients who underwent hepatic resection or radiofrequency ablation for initial HCC. Patients were divided into four groups. Thirty had high serum HBV DNA levels (>4 log(10) copies/mL) and had not received antiviral therapy (high virus group; HVG). Thirty-four had low HBV DNA levels (< or =4 log(10) copies/mL) and had not received antiviral therapy (low virus group; LVG). Twenty received antiviral therapy after HCC developed (therapeutic group A, TG-A). Nineteen received antiviral therapy before HCC developed (therapeutic group B, TG-B). RESULTS: Cumulative HCC recurrence rates at 3 years in the HVG, LVG, TG-B, and TG-A were 71.1%, 42.2%, 42.3%, and 52.0%, respectively. Recurrence rates differed significantly between the HVG and LVG (P = 0.016) and between the HVG and TG-B (P = 0.008). Recurrence rate in the TG-A was marginally lower than in the HVG (P = 0.10). On multivariate analysis, high serum hepatitis B virus DNA levels (hazard ratio: HR 2.67; 95% CI 1.31-5.47; P = 0.007) and absence of antiviral therapy (HR 2.57; 95% CI 1.34-4.94; P = 0.005) were independent risk factors for hepatocellular carcinoma recurrence. CONCLUSION: HBV DNA level and antiviral therapy are associated with HCC recurrence. For patients with high HBV DNA levels, antiviral therapy before the development of HCC is important for prevention of recurrence.