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PMID:20562916

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Citation

Shang, X, Vasudevan, SA, Yu, Y, Ge, N, Ludwig, AD, Wesson, CL, Wang, K, Burlingame, SM, Zhao, YJ, Rao, PH, Lu, X, Russell, HV, Okcu, MF, Hicks, MJ, Shohet, JM, Donehower, LA, Nuchtern, JG and Yang, J (2010) Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma. Oncogene 29:4938-46

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.

Links

PubMed Online version:10.1038/onc.2010.244

Keywords

Apoptosis/drug effects; Cell Line, Tumor; Doxorubicin/pharmacology; Drug Resistance, Neoplasm; Dual-Specificity Phosphatases/genetics; Dual-Specificity Phosphatases/metabolism; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinase Phosphatases/genetics; Mitogen-Activated Protein Kinase Phosphatases/metabolism; Neuroblastoma/enzymology; Neuroblastoma/genetics; Neuroblastoma/metabolism; Neuroblastoma/pathology; Phosphorylation; Serine/metabolism; Tumor Suppressor Protein p53/antagonists & inhibitors; Tumor Suppressor Protein p53/chemistry; Tumor Suppressor Protein p53/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BV47

F

Seeded From UniProt

complete

HUMAN:DUS26

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:DUS26

enables

GO:0008138: protein tyrosine/serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:DUS26

enables

GO:0002039: p53 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BV47

F

Seeded From UniProt

complete


See also

References

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