title: Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation.
abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.
authors.affiliation: Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Jesmin
authors.initials: J
authors.lastname: Akter
authors.affiliation: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. Electronic address: atakatori@chiba-cc.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takatori
authors.affiliation: Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Md Sazzadul
authors.initials: MS
authors.lastname: Islam
authors.affiliation: Department of Pathology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakazawa
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. Electronic address: tozaki@chiba-cc.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Saga Medical Centre, 840-8571, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D014212:Tretinoin / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: C494422:LRRN3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D014212:Tretinoin; D053829:Amyloid Precursor Protein Secretases
keywords: ATRA; Differentiation; NLRR3; Neuroblastoma; Secretase