Regulation and function of p52 and Bcl-3 NF-kB subunit complexes. (360G-Wellcome-094409_Z_10_Z)

Activation of the 'alternative' (non-canonical) NF-kB pathway leads to processing of the p100 precursor subunit to p52. Activated p52 containing complexes, together with the p52 coactivator Bcl-3, regulate the adaptive immune response and recent studies have demonstrated the importance of this pathway in many diseases, including cancer. However, the functional differences between different p52 containing complexes are poorly understood, while the role of different post-translational modificatio ns has not been defined. We propose that the p52 homodimer/Bcl-3 complex has particular importance as a pro-proliferative, pro-metastatic and tumour promoting transcription factor, particularly in breast cancer. Importantly, recent evidence suggests that formation of this complex is regulated by p52 phosphorylation. By complementing the expertise of the applicants' laboratories, we plan to transform our understanding of the function of p52 and Bcl-3 NF-kB complexes by linking state of the art mechanistic analysis to physiological significance and disease progression. Specifically we will (1) Investigate the regulation and function of the p52/Bcl-3 complex (2) Develop novel knock-in mouse models to allow us to investigate p52 function in vivo (3) Define the role of p52 and Bcl-3 in breast cancer and determine their ability to act as disease modifiers