Nucleolar GTP-binding Protein-1 (NGP-1) Promotes G1 to S Phase Transition by Activating Cyclin-dependent Kinase Inhibitor p21Cip1/Waf1

Background: Breast cancer autoantigen nucleolar GTP-binding protein-1 (NGP-1) is overexpressed in cancers. Results: NGP-1 promotes G(1) to S phase transition by modulating the p53/p21 pathway. Conclusion: CDK inhibitor, p21, enhances cell proliferation in certain situations. Significance: This study provides evidence that p21 induces cell proliferation in addition to its traditional tumor suppressor function.Nucleolar GTP-binding protein (NGP-1) is overexpressed in various cancers and proliferating cells, but the functional significance remains unknown. In this study, we show that NGP-1 promotes G(1) to S phase transition of cells by enhancing CDK inhibitor p21(Cip-1/Waf1) expression through p53. In addition, our results suggest that activation of the cyclin D1-CDK4 complex by NGP-1 via maintaining the stoichiometry between cyclin D1-CDK4 complex and p21 resulted in hyperphosphorylation of retinoblastoma protein at serine 780 (p-RBSer-780) followed by the up-regulation of E2F1 target genes required to promote G(1) to S phase transition. Furthermore, our data suggest that ribosomal protein RPL23A interacts with NGP-1 and abolishes NGP-1-induced p53 activity by enhancing Mdm2-mediated p53 polyubiquitination. Finally, reduction of p-RBSer-780 levels and E2F1 target gene expression upon ectopic expression of RPL23a resulted in arrest at the G(1) phase of the cell cycle. Collectively, this investigation provides evidence that NGP-1 promotes cell cycle progression through the activation of the p53/p21(Cip-1/Waf1) pathway.