title: Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells.
abstract: Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumor glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors up-regulate Mcl-1 contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is overexpressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. Herein we have found that Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia induced cell death. This cell death is reduced by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3 induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells. These results suggest that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumors.
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Henson
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xiao
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.
authors.forename: Epsita
authors.initials: E
authors.lastname: Shome
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
authors.forename: Meghan B
authors.initials: MB
authors.lastname: Azad
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
authors.forename: Teralee R
authors.initials: TR
authors.lastname: Burton
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Queau
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.
authors.forename: Akshay
authors.initials: A
authors.lastname: Sathya
authors.affiliation: c Faculty of Medicine and Dentistry, University of Alberta , Edmonton Canada.|d Departments of Pediatrics, Medical Genetics and Oncology , University of Alberta , Edmonton , Canada.
authors.forename: David D
authors.initials: DD
authors.lastname: Eisenstat
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Canada.
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016923:Cell Death; D015687:Cell Hypoxia; D002470:Cell Survival; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C090121:BNIP3 protein, human; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases
keywords: BNIP3; EGFR; Mcl-1; glioma cells; hypoxia and