| Autor: |
Maietta I; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Napoli, Italy.; Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples 'Federico II', Via S. Pansini 5, 80131 Naples, Italy., Del Peschio F; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Napoli, Italy.; Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples 'Federico II', Via S. Pansini 5, 80131 Naples, Italy., Buonocore P; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Napoli, Italy.; Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples 'Federico II', Via S. Pansini 5, 80131 Naples, Italy., Viscusi E; Complex Operative Unit, Pathological Anatomy, Pellegrini Hospital ASL NA1, 80134 Naples, Italy., Laudati S; Complex Operative Unit, Pathological Anatomy 'Ospedale del Mare' ASL NA1 80147 Naples, Italy., Iannaci G; Complex Operative Unit, Pathological Anatomy, Pellegrini Hospital ASL NA1, 80134 Naples, Italy., Minopoli M; Preclinical Models of Tumor Progression, Department of Translational Research Supporting Oncological Pathways-National Cancer Institute of Naples, IRCCS 'G. Pascale' Via M. Semmola, 80131 Naples, Italy., Motti ML; Department of Movement Sciences and Wellbeing, University 'Parthenope', Via Medina 40, 80133 Naples, Italy., De Falco V; Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Napoli, Italy.; Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples 'Federico II', Via S. Pansini 5, 80131 Naples, Italy. |
| Abstrakt: |
The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 both in vitro and in vivo by kinase assay, immunoblot, and co-immunoprecipitation assay; this phosphorylation increases the stability of MDM2 which in turn binds p53, ubiquitinating it and promoting its degradation by proteasome. A pharmacological inhibitor of p90RSK, BI-D1870, decreases MDM2 phosphorylation, and restores p53 function, which in turn transcriptionally increases the expression of cell cycle inhibitor p21 and of pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2, causing a block of cell proliferation, measured by a BrdU assay and growth curve, and promoting apoptosis, measured by a TUNEL assay. Finally, an immunohistochemistry evaluation of primary thyroid tumors, in which p90RSK is very active, confirms MDM2 stabilization mediated by p90RSK phosphorylation. |
