Making Life or Death Choices with CBP

Abstract

The transcriptional coactivator CBP (CREB-binding protein) can interact with p53, and thereby promote apoptosis, or with the functionally antagonistic transcription factor nuclear factor κB (NF-κB), and thereby promote cell proliferation. Huang et al . found that tumor necrosis factor-α (TNF-α) not only enhanced CBP association with the NF-κB p65 subunit (as previously shown) and CBP recruitment to NF-κB-responsive promoters but also decreased CBP binding to p53 and its association with p53-responsive promoters. These effects were reversed by inhibiting IKK (inhibitor of NF-κB kinase), which is involved in NF-κB activation. Similarly, in mouse embryonic fibroblasts lacking IKKα, TNF-α failed to stimulate CBP association with p65, despite translocation of p65 to the nucleus, but instead stimulated its association with p53. In vitro kinase assays combined with mutational analysis indicated that IKKα phosphorylated CBP on serine residues 1382 and 1386; moreover, TNF-α stimulated IKKα-dependent phosphorylation of CBP on Ser 1382 and Ser 1386 in HeLa cells. Furthermore, IKKα-dependent phosphorylation of CBP on Ser 1382 and Ser 1386 enhanced CBP binding to p65, thereby decreasing its association with p53, a shift that led to an increase in the transcription of NF-κB-responsive genes and a decrease in the transcription of p53 targets. A comparison of human lung cancer and adjacent nonmalignant tissue indicated that IKKα activation was associated with increased phosphorylation of CBP at Ser 1382 and Ser 1386 . Stable transfection of wild-type or mutant CBP indicated that CBP phosphorylation on Ser 1382 and Ser 1386 mediated TNF-α-dependent stimulation of cell proliferation. Thus, the authors conclude that CBP phosphorylation by IKKα promotes CBP binding to NF-κB rather than p53, an effect that may be critical to the choice between proliferation and apoptosis. W.-C. Huang, T.-K. Ju, M.-C. Hung, C.-C. Chen, Phosphorylation of CBP by IKKα promotes cell growth by switching the binding preference of CBP from p53 to NF-κB. Mol. Cell 26 , 75-87 (2007). [Online Journal]