β-Catenin Regulates Hepatic Mitochondrial Function and Energy Balance in Mice

Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia

“…LSCs in AML rely primarily on OXPHOS to generate ATP for energy (10), and our results show that Gaq inhibition can impair the energy-generating capacity of MLL leukemic cells, increase ROS levels and lead to activation of a stress response associated with activation of Gadd45a. Our data revealing reduced β-catenin levels following Gaq inhibition are consistent with the effects of Gaq on mitochondrial activity being mediated via β-catenin activity, as recent studies have shown the crucial role for β-catenin in mitochondrial energy metabolism (11,12), and β-catenin is also critical in HSC for suppression of ROS levels (12). MLL AML has a particular dependence on β-catenin activity (1) and the findings presented here raise the possibility that targeting of -catenin and mitochondrial metabolism via Gaq may be a potential approach to reduction of leukemogenesis in MLL AML.…”

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

“…To activate canonical Wnt/␤-catenin signaling, we used the plasmid pcDNA3S33Y, resulting in robust TCF 3 -dependent transcriptional activation compared with wild-type ␤-catenin (25). To inhibit canonical Wnt/␤-catenin signaling, a retroviral expression vector containing a mutant TCF4 expression cassette lacking the ␤-catenin binding domain retains DNA binding activity and thus functions in a dominant negative fashion as described previously (11,26).…”

“…To investigate the effects of Wnt/␤-catenin signaling on cell survival, we generated ␤-catenin mutants from mouse AML12 hepatocytes with ␤-catenin loss (dnTCF) or gain (S33Y) of function (11,12,25,26). S33Y mutants demonstrate heightened TCF signaling, mild increase in ␤-catenin protein, and increased proliferation ( Fig.…”

“…We have recently found an additional role for ␤-catenin regulating hepatic energy metabolism and mitochondrial function (11). Furthermore, we have previously shown a protective role of ␤-catenin in the ischemic liver through binding to HIF-1␣ (hypoxia-inducible factor 1␣) (12) to promote cell survival.…”

Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis

“…The role of Wnt signaling has been intensively studied in many tissues, including the liver, using various transgenic animal models. Although overexpression of a given Wnt ligand or the expression of constitutively active S33Y mutant b-cat has provided solid evidence for the involvement of this signaling cascade in liver development, zonation, cell proliferation, tumorigenesis, and the susceptibility to oxidative stress (21)(22)(23)(24)(25)(26), the hepatic role of Wnt signaling in metabolic homeostasis still remains unclear. The complexity of the Wnt signaling pathway is reflected by the existence of multiple Wnt ligands, receptors, and coreceptors, as well as various intracellular modulating elements (27,28).…”