Nucleophosmin/B23, a multifunctional protein that can regulate apoptosis

Nucleophosmin (NPM)/B23, a multifunctional nucleolar protein, is overexpressed in actively proliferating cells and cancer cells. B23 is a tumor marker and exerts its oncogenic effect through binding and suppressing numerous tumor suppressors. NPM-ALK, an aberrant fusion protein produced from t(2;5) translocation in anaplastic large cell lymphoma (ALCL), fuses the N-terminus of B23 to the intracellular tyrosine kinase domain of ALK, provoking lymphomas by stimulating various mitogenic proteins including PI 3-kinase and PLC-gamma 1. Overexpression of B23 inhibits apoptosis, while knockdown of B23 induces cell death. However, whether B23 is directly involved in blocking apoptotic machinery remains elusive. B23 is recently identified as a nuclear PI(3,4,5)P-3 binding protein through a PI(3,4,5)P-3 column and NGF-treated PC12 nuclear extracts. B23 has been shown to mediate the anti-apoptotic effects of NGF by inhibiting DNA fragmentation activity of CAD. B23 mutants that cannot associate with PI(3,4,5)P-3 fail to prevent DNA fragmentation, indicating that PI(3,4,5)P-3/B23 complex regulates the anti-apoptotic activity of NGF in the nucleus. Identification of a small molecule mediating the anti-apoptotic action of B23 unveils a novel therapeutic target for treatment of B23 amplified cancers.