title: The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose.
abstract: The BH3-only protein, Noxa, is induced in response to apoptotic stimuli, such as DNA damage, hypoxia, and proteasome inhibition in most human cells. Noxa is constitutively expressed in proliferating cells of hematopoietic lineage and required for apoptosis in response to glucose stress. We show that Noxa is phosphorylated on a serine residue (S(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify Cdk5 as the Noxa kinase and show that Cdk5 knockdown or expression of a Noxa S(13) to A mutant increases sensitivity to glucose starvation, confirming that the phosphorylation is protective. Both glucose deprivation and Cdk5 inhibition promote apoptosis by dephosphorylating Noxa. Paradoxically, Noxa stimulates glucose consumption and may enhance glucose turnover via the pentose phosphate pathway rather than through glycolysis. We propose that Noxa plays both growth-promoting and proapoptotic roles in hematopoietic cancers with phospho-S(13) as the glucose-sensitive toggle switch controlling these opposing functions.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xazmin H
authors.initials: XH
authors.lastname: Lowman
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McDonnell
authors.forename: Ashley
authors.initials: A
authors.lastname: Kosloske
authors.forename: Oludare A
authors.initials: OA
authors.lastname: Odumade
authors.forename: Christopher
authors.initials: C
authors.lastname: Jenness
authors.forename: Christine B
authors.initials: CB
authors.lastname: Karim
authors.forename: Ronald
authors.initials: R
authors.lastname: Jemmerson
authors.forename: Ameeta
authors.initials: A
authors.lastname: Kelekar
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051360:Cyclin-Dependent Kinase 5; D005947:Glucose