Nuclear GRP75 binds retinoic acid receptors to promote neuronal differentiation of neuroblastoma
Journal
PLoS ONE
Journal Volume
6
Journal Issue
10
Pages
e26236
Date Issued
2011
Author(s)
YU-YIN SHIH
Nakagawara, Akira
Tsay, Yeou-Guang
Liao Y.-F.
Abstract
Retinoic acid (RA) has been approved for the differentiation therapy of neuroblastoma (NB). Previous work revealed a correlation between glucose-regulated protein 75 (GRP75) and the RA-elicited neuronal differentiation of NB cells. The present study further demonstrated that GRP75 translocates into the nucleus and physically interacts with retinoid receptors (RARα and RXRα) to augment RA-elicited neuronal differentiation. GRP75 was required for RARα/RXRα-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARα/RXRαin a RA-dependent manner. More intriguingly, the level of GRP75/RARα/RXRα tripartite complexes was tightly associated with the RA-induced suppression of tumor growth in animals and the histological grade of differentiation in human NB tumors. The formation of GRP75/RARα/RXRα complexes was intimately correlated with a normal MYCN copy number of NB tumors, possibly implicating a favorable prognosis of NB tumors. The present findings reveal a novel function of nucleus-localized GRP75 in actively promoting neuronal differentiation, delineating the mode of action for the differentiation therapy of NB by RA. ? 2011 Shih et al.
SDGs
Other Subjects
glucose regulated protein 75; proteasome; protein; retinoic acid; retinoic acid receptor; retinoic acid receptor alpha; retinoid X receptor alpha; unclassified drug; glucose regulated proteins; glucose-regulated proteins; heat shock protein 70; membrane protein; MYCN protein, human; nuclear protein; oncoprotein; retinoic acid; retinoic acid receptor; animal experiment; animal model; article; cancer inhibition; cancer therapy; cell nucleus; clinical article; complex formation; controlled study; gene dosage; human; human cell; human tissue; male; mouse; nerve cell differentiation; neuroblastoma; nonhuman; prognosis; protein degradation; protein interaction; protein localization; protein transport; transcription regulation; tumor differentiation; animal; cell differentiation; cell nucleus; DNA responsive element; down regulation; drug effect; drug screening; genetics; metabolism; nerve cell; neuroblastoma; pathology; protein binding; protein multimerization; signal transduction; treatment outcome; Animalia; Animals; Cell Differentiation; Cell Nucleus; Down-Regulation; Gene Dosage; HSP70 Heat-Shock Proteins; Humans; Membrane Proteins; Mice; Neuroblastoma; Neurons; Nuclear Proteins; Oncogene Proteins; Proteasome Endopeptidase Complex; Protein Binding; Protein Multimerization; Protein Transport; Proteolysis; Receptors, Retinoic Acid; Response Elements; Signal Transduction; Treatment Outcome; Tretinoin; Xenograft Model Antitumor Assays
Type
journal article