PMID: 19202066

 

    Legend: Sugar

Title : Loss of p53 enhances catalytic activity of IKKbeta through O-linked beta-N-acetyl glucosamine modification.

Abstract :

1. The IkappaB kinase ( IKK )- NF-kappaB pathway plays a critical role in oncogenesis
2. Recently, we have shown that p53 regulates glucose metabolism through the IKK- NF-kappaB pathway and that, in the absence of p53 , the positive feedback loop between IKK- NF-kappaB and glycolysis has an integral role in oncogene-induced cell transformation
3. Here, we demonstrate that IKKbeta , a component of the IKK complex, was constitutively modified with O-linked beta-N-acetyl glucosamine (O-GlcNAc) in both p53-deficient mouse embryonic fibroblasts (MEFs) and transformed human fibroblasts
4. In p53-deficient cells, the O-GlcNAcylated IKKbeta and the activating phosphorylation of IKK were decreased by p65 / NF-kappaB knockdown or glucose depletion.
5. We also found that high glucose induced the O-GlcNAcylation of IKKbeta and sustained the TNFalpha-dependent IKKbeta activity
6. Moreover, the O-GlcNAcase inhibitor streptozotocin intensified O-GlcNAcylation and concomitant activating phosphorylation of IKKbeta
7. Mutational analysis revealed that O-GlcNAcylation of IKKbeta occurred at Ser 733 in the C-terminal domain , which was identified as an inactivating phosphorylation site , suggesting that IKKbeta O-GlcNAcylation regulates its catalytic activity
8. Taken together, we propose a novel mechanism for the enhancement of NF-kappaB activity by loss of p53 , which evokes positive feedback regulation from enhanced glucose metabolism to IKK in oncogenesis