title: GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb.
abstract: Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3β regulates the survival of leukemia cells. We demonstrate that upon GSK3β kinase inhibition different types of leukemia cells show severe proliferation defects as a result of apoptosis. The transcription factor c-Myb is found to be the main target of GSK3β inhibition in cell survival. GSK3β inactivation reduces the expression of c-Myb by promoting its ubiquitination-mediated degradation, thereby inhibiting the expression of c-Myb-dependent antiapoptotic genes Bcl2 and survivin. Coimmunoprecipitation, reporter assays, chromatin immunoprecipitation, and knockdown studies show that c-Myb needs to interact and cooperate with transcription factor LEF-1 in the activation of Bcl2 and survivin and that both transcription factors are required for cell survival. These data reveal an as-yet-unknown mechanism by which GSK3β controls cell survival.
authors.affiliation: Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D017209:Apoptosis; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007938:Leukemia; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D011485:Protein Binding; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism / Q000502:physiology*; D000077022:Survivin; D054875:Ubiquitination
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C107489:BIRC5 protein, human; C501126:DKK1 protein, human; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D008301:Maleimides; D019253:Proto-Oncogene Proteins c-bcl-2; D020598:Proto-Oncogene Proteins c-myb; C417521:SB 216763; D000077022:Survivin; D049410:Luciferases, Renilla; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3