Nuclear GRP75 binds retinoic acid receptors to promote neuronal differentiation of neuroblastoma.
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.
Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Yu-Yin
YY
Shih
Hsinyu
H
Lee
Akira
A
Nakagawara
Hseuh-Fen
HF
Juan
Yung-Ming
YM
Jeng
Yeou-Guang
YG
Tsay
Dong-Tsamn
DT
Lin
Fon-Jou
FJ
Hsieh
Chien-Yuan
CY
Pan
Wen-Ming
WM
Hsu
Yung-Feng
YF
Liao
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D018628:Gene Dosage; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D018840:HSP70 Heat-Shock Proteins; C459801:MYCN protein, human; D008565:Membrane Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D018168:Receptors, Retinoic Acid; C018551:glucose-regulated proteins; D014212:Tretinoin; D046988:Proteasome Endopeptidase Complex