論文 - 詳細
RRC ID | 44980 |
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著者 | Iwao C, Shidoji Y. |
タイトル | Induction of nuclear translocation of mutant cytoplasmic p53 by geranylgeranoic acid in a human hepatoma cell line. |
ジャーナル | Sci Rep |
Abstract |
Mutant p53 proteins in human hepatoma cell lines such as HuH-7 (Y220C) and PLC/PRF/5 (R249S) accumulate in the cytoplasm, and lose their transcriptional function. Geranylgeranoic acid (GGA) is a naturally occurring acyclic diterpenoid that induces cell death in both cell lines, but not in HepG2 cells harboring wild-type p53. Here, we demonstrate that micromolar concentrations of GGA induce a rapid nuclear translocation of cytoplasmic p53 in both p53-mutant cell lines and p53 knockdown attenuates GGA-induced cell death in HuH-7 cells. Cell-free experiments demonstrate that GGA is able to release 670-kD p53-containing complexes from putative huge macromolecular aggregates in post-mitochondrial fractions as revealed on blue-native gradient PAGE. Among several p53-target genes tested, GGA upregulates PUMA gene expression, and ivermectin, an inhibitor for importin α/β, blocks GGA-induced nuclear translocation of cytoplasmic p53 and suppresses GGA-induced upregulation of PUMA mRNA levels in HuH-7 cells. Taken together, these data suggest that GGA treatment stimulates a nuclear translocation of mutant p53 through its dissociation from cytoplasmic aggregates, which may be essential for GGA-induced cell death. |
巻・号 | 4 |
ページ | 4419 |
公開日 | 2014-3-24 |
DOI | 10.1038/srep04419 |
PII | srep04419 |
PMID | 24658405 |
PMC | PMC3963086 |
MeSH | Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis Regulatory Proteins / agonists Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism Cell Line, Tumor Cell Nucleus / drug effects Cell Nucleus / ultrastructure Cytosol / drug effects Cytosol / ultrastructure Diterpenes / pharmacology* Gene Expression Regulation, Neoplastic* Hepatocytes / drug effects* Hepatocytes / metabolism Hepatocytes / pathology Humans Ivermectin / pharmacology Protein Transport / drug effects Proto-Oncogene Proteins / agonists Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Signal Transduction Tumor Suppressor Protein p53 / antagonists & inhibitors Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism alpha Karyopherins / antagonists & inhibitors alpha Karyopherins / genetics alpha Karyopherins / metabolism beta Karyopherins / antagonists & inhibitors beta Karyopherins / genetics beta Karyopherins / metabolism |
IF | 3.998 |
引用数 | 11 |
WOS 分野 | CELL BIOLOGY |
リソース情報 | |
ヒト・動物細胞 | HuH-7 Hep G2 |