Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB.
CBP plays a central role in coordinating and integrating multiple signaling pathways. Competition between NF-kappaB and p53 for CBP is a crucial determinant of whether a cell proliferates or undergoes apoptosis. However, how the CBP-dependent crosstalk between these two transcription factors is regulated remains unclear. Here, we show that IKKalpha phosphorylates CBP at serine 1382 and serine 1386 and consequently increases CBP's HAT and transcriptional activities. Importantly, such phosphorylation enhances NF-kappaB-mediated gene expression and suppresses p53-mediated gene expression by switching the binding preference of CBP from p53 to NF-kappaB, thus promoting cell growth. The CBP phosphorylation also correlates with constitutive IKKalpha activation in human lung tumor tissue compared with matched nontumor lung tissue. Our results suggest that phosphorylation of CBP by IKKalpha regulates the CBP-mediated crosstalk between NF-kappaB and p53 and thus may be a critical factor in the promotion of cell proliferation and tumor growth.
Huang
Wei-Chien
WC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Ju
Tsai-Kai
TK
Hung
Mien-Chie
MC
Chen
Ching-Chow
CC
D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus; D049109:Cell Proliferation; D016384:Consensus Sequence; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000209:etiology; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016328:NF-kappa B; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012694:Serine; D050882:CREB-Binding Protein; D051550:I-kappa B Kinase