B55α is induced upon glutamine deprivation to promote p53 activation and cell survival.
Major finding: B55α is induced upon glutamine deprivation to promote p53 activation and cell survival.
Clinical relevance: Glutamine levels are significantly reduced in the cores of growing tumors.
Impact: Adaptive PP2A complexes form to mediate signaling in response to specific cellular stresses.
Rapidly proliferating cancer cells are dependent on glutamine, a crucial source of carbon and nitrogen for amino acids, nucleotides, tricarboxylic acid cycle intermediates, and intracellular antioxidants. Cancer cells must adapt to periods of glutamine depletion due to increased glutamine catabolism during tumor growth, but the signaling pathways that promote survival under these conditions remain unclear. Studies in yeast have indicated that the serine/threonine phosphatase protein phosphatase 2A (PP2A) plays a key role in sensing cellular glutamine levels. In humans, PP2A is a collection of over 60 heterotrimeric enzymes with diverse targets and cellular functions that consist of 1 of 2 scaffolding “A” subunits, 1 of at least 16 regulatory “B” subunits that determine specificity and subcellular localization, and 1 of 2 catalytic “C” subunits. Reid and colleagues evaluated the expression of all PP2A subunits following glutamine deprivation in mouse fibroblasts and found that only the regulatory subunit B55α was strongly and selectively upregulated and incorporated into PP2A complexes in response to glutamine withdrawal and subsequent accumulation of reactive oxygen species. Cell survival upon glutamine deprivation was dependent on phosphorylation and activation of p53, which required B55α. Peptide sequencing of B55α-interacting proteins identified EDD, a known negative regulator of p53 that blocks its phosphorylation. B55α bound EDD and maintained it in a dephosphorylated inactive state, which promoted p53 activation. B55α induction also promoted the survival of cancer cells upon glutamine depletion in vitro and was required for the growth of tumors, which showed low glutamine levels and high B55α expression in their cores compared with their peripheries. These findings provide insight into how cancer cells can adapt to glutamine-poor conditions and suggest that adaptive PP2A complexes can play important roles in cellular responses to metabolic stress.