Nuclear import of transcriptional corepressor BCOR occurs through interaction with karyopherin α expressed in human periodontal ligament.

Abstract

Mutations in the gene encoding BCL-6 corepressor (BCOR) are responsible for oculofaciocardiodental (OFCD) syndrome, which is a rare X-linked dominant disorder characterized by radiculomegaly of permanent teeth as the most typical symptom. To function as a transcriptional corepressor, BCOR needs to enter the nucleus; however, the molecular pathway for its nuclear translocation during dental root formation remains unclear. The purpose of this study was to determine the mechanism underlying BCOR transport into the nucleus. Our results showed that human periodontal ligament (PDL) cells expressed karyopherin α (KPNA)2, KPNA4, and KPNA6 belonging to a family of nuclear import proteins, which interacted with BCOR in the immunoprecipitation assay. Site-directed mutagenesis targeting the two nuclear localization signals (NLSs) within BCOR reduced its nuclear translocation; however, co-expression of KPNA2, KPNA4, or KPNA6 with BCOR carrying a previously described mutation which eliminated one of the two NLSs significantly increased nuclear accumulation of the mutant BCOR, indicating participation of KPNA in BCOR nuclear translocation. Comparative expression profiling of PDL cells isolated from normal and OFCD patients revealed significant downregulation of SMAD4, GLI1, and nuclear factor 1-C (NFIC) mRNA expression, suggesting that BCOR mutations cause hyperactive root formation in OFCD syndrome by inhibiting SMAD4-Hedgehog-NFIC signaling implicated in dental root development. Our study contributes to understanding of the mechanisms providing nuclear import of BCOR during root formation.

• Authors: Aung Bhone Myat, Takuya Ogawa, Chiho Kadota-Watanabe, Keiji Moriyama
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 507 Issue 1-4 Pg. 67-73 (12 09 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 30396568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• BCOR protein, human
• KPNB1 protein, human
• Mutant Proteins
• Nuclear Localization Signals
• Proto-Oncogene Proteins
• Repressor Proteins
• alpha Karyopherins
• beta Karyopherins

Topics

• Active Transport, Cell Nucleus
• Adolescent
• Adult
• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• COS Cells
• Cell Nucleus (metabolism)
• Child
• Chlorocebus aethiops
• Down-Regulation (genetics)
• Humans
• Male
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Nuclear Localization Signals (metabolism)
• Periodontal Ligament (metabolism)
• Protein Binding
• Proto-Oncogene Proteins (chemistry, genetics, metabolism)
• Repressor Proteins (chemistry, genetics, metabolism)
• Subcellular Fractions (metabolism)
• Transcription, Genetic
• alpha Karyopherins (metabolism)
• beta Karyopherins (metabolism)