The fusion oncoprotein PML-RARalpha induces endoplasmic reticulum (ER)-associated degradation of N-CoR and ER stress.
PML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha), causes acute promyelocytic leukemias (APL). Although the role of nuclear PML-RARalpha has been extensively studied, a significant amount of PML-RARalpha is in the cytoplasm. The role cytoplasmic PML-RARalpha plays in leukemogenesis is unknown. Here we report that PML-RARalpha induces the N-CoR accumulation in the endoplasmic reticulum (ER), leading to the induction of ER stress and the processing of activating transcription factor 6 (ATF6), the unfolded protein response. PML-RARalpha stimulates the ubiquitylation of N-CoR via Ubc6 that is involved in the protein quality control. This ER-associated degradation (ERAD) of N-CoR reduces the soluble N-CoR protein levels in the nucleus. The two N-CoR-interacting sites in PML-RARalpha are required for the ERAD of N-CoR, suggesting the aberrant binding of PML-RARalpha to N-CoR may induce the ERAD of N-CoR. Overexpression of N-CoR induces the differentiation of APL-derived NB4 cells, suggesting that the low levels of N-CoR in the nucleus may contribute at least partly to PML-RARalpha-mediated leukemogenesis.
Khan
Md Matiullah
MM
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
Nomura
Teruaki
T
Chiba
Tomoki
T
Tanaka
Keiji
K
Yoshida
Hiderou
H
Mori
Kazutoshi
K
Ishii
Shunsuke
S
D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*
C539127:NCOR1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein