ABSTRACT
Chemoresistance is a major cause of treatment failure and poor outcome in neuroblastoma. In this study, we investigated the expression and function of dual-specificity phosphatase 26 (DUSP26), also known as mitogen-activated protein kinase phophatase-8, in human neuroblastoma. We found that DUSP26 was expressed in a majority of neuroblastoma cell lines and tissue specimens. Importantly, we found that DUSP26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis. In contrast, DUSP26 overexpression in the SK-N-SH cell line inhibited doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression and apoptosis. Using in vitro and in vivo assays, we found that DUSP26 binds to p53 and dephosphorylates p53 at Ser20 and Ser37. In this report, we show that DUSP26 functions as a p53 phosphatase, which suppresses downstream p53 activity in response to genotoxic stress. This suggests that inhibition of this phosphatase may increase neuroblastoma chemosensitivity and DUSP26 is a novel therapeutic target for this aggressive pediatric malignancy.
Subject(s)
Dual-Specificity Phosphatases/metabolism , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Neuroblastoma/enzymology , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Dual-Specificity Phosphatases/genetics , Gene Expression Regulation, Neoplastic , Humans , Mitogen-Activated Protein Kinase Phosphatases/genetics , Neuroblastoma/genetics , Neuroblastoma/metabolism , Neuroblastoma/pathology , Phosphorylation , Serine/metabolism , Tumor Suppressor Protein p53/chemistryABSTRACT
This investigation focused on the effects of two independent variables: (a) teacher-developed goals and monitoring systems versus a curriculum-based measurement (CBM) goal and monitoring system; and (b) individual expert versus group follow-up consultation. The dependent data were academic achievement measures. Subjects were 55 special education, elementary school students with mild and moderate disabilities randomly assigned to one of four treatment conditions: A, teacher-developed goal and progress monitoring with individual expert follow-up consultation; B, CBM goal and progress monitoring with individual expert follow-up consultation; C, teacher-developed goal and progress monitoring with group follow-up consultation; and D, CBM goal and progress monitoring with group follow-up consultation. Results showed that groups employing CBM and group consultation generally out-performed the other groups. Implications included expanded use of CBM goals and progress monitoring and continued study of collaboration as a method of CBM program implementation.
