The Proapoptotic Function of Noxa in Human Leukemia Cells Is Regulated by the Kinase Cdk5 and by Glucose

Xazmin H. Lowman, Maureen A. McDonnell, Ashley Kosloske, Oludare A. Odumade, Christopher Jenness, Christine B. Karim, Ronald Jemmerson, Ameeta Kelekar

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119 Scopus citations


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 (S13) 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 S13 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-S13 as the glucose-sensitive toggle switch controlling these opposing functions.

Original languageEnglish (US)
Pages (from-to)823-833
Number of pages11
JournalMolecular Cell
Issue number5
StatePublished - Dec 10 2010

Bibliographical note

Funding Information:
The authors thank Dr. Jeffrey Miller as well as the Tissue Procurement Facility in the Masonic Cancer Center at the University of Minnesota for providing deidentified patient leukemia cells, the Flow Cytometry core facilities for help with data collection and analysis, John Oja from the Biomedical Image Processing Laboratory (BIPL) for help with confocal and fluorescence microscopy, and Tad George and AMNIS Corporation for help with Imaging Flow Cytometry data collection and analysis. We also thank Dr. Kristin Hogquist for helpful advice on the primary T cell experiments, Dr. M.J. Abedin for assistance with protein purification, and Christopher Valley and Lamya Yamani for helpful discussions. X.H.L. and O.A.O. were supported by National Institutes of Health Grants T32-CA009138 (to X.H.L. and O.A.O.) and F31-AI084524 (to O.A.O.). C.B.K. was supported in part by National Institutes of Health Grant GM27906. This research was primarily funded through grants from the Elsa U. Pardee Foundation, the Leukemia Research Foundation, and the Minnesota Medical Foundation (to A.K.).


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