PMID:21145489

Citation	Lowman, XH, McDonnell, MA, Kosloske, A, Odumade, OA, Jenness, C, Karim, CB, Jemmerson, R and Kelekar, A (2010) The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose. Mol. Cell 40:823-33
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.
Links	PubMed Online version:10.1016/j.molcel.2010.11.035
Keywords	Apoptosis/physiology; Cell Line, Tumor; Cyclin-Dependent Kinase 5/genetics; Cyclin-Dependent Kinase 5/metabolism; Glucose/metabolism; Humans; Leukemia/enzymology; Leukemia/metabolism; Phosphorylation; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MCL1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q13794	F		Seeded From UniProt	complete
HUMAN:APR	involved_in	GO:0010907: positive regulation of glucose metabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:APR	part_of	GO:0005829: cytosol	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:APR	involved_in	GO:0042149: cellular response to glucose starvation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:APR	involved_in	GO:0043065: positive regulation of apoptotic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:APR	part_of	GO:0005739: mitochondrion	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:APR	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q07820-1	F		Seeded From UniProt	complete
HUMAN:CDK5	involved_in	GO:0018105: peptidyl-serine phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:CDK5	enables	GO:0004674: protein serine/threonine kinase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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