論文 - 詳細
| RRC ID | 64397 |
|---|---|
| 著者 | Hasegawa-Ogawa M, Okano HJ. |
| タイトル | Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein. |
| ジャーナル | Sci Rep |
| Abstract |
TAR DNA-binding protein (TDP-43, encoded by TARDBP) is a multifunctional protein that regulates transcription and RNA metabolism by binding DNA or RNA. TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) because abnormal accumulation of cleaved and phosphorylated C-terminal fragments of TDP-43 in motor neurons is a pathological hallmark of ALS. Here, we cloned and analyzed the promoter region of the TARDBP gene. TARDBP upstream sequences and/or intron/luciferase constructs were generated, and their promoter activity was experimentally assessed. The upstream region predictably exhibited promoter activity and identified putative cis-acting elements, including the i-motif, was relevant for the regulation of TDP-43 expression. The cellular abundance of TDP-43 is strictly controlled, and its constancy is critically important for motor neuron survival. A machinery serving to maintain a constant level of TDP-43 is autoregulation via control of mRNA stability, a negative feedback system involving binding to the 3' untranslated region of its own pre-mRNA. However, whether transcriptional mechanisms contribute to TDP-43 autoregulation is unclear. We further showed that TDP-43 negatively regulates the TARDBP promoter and, surprisingly, that disease-causing TDP-43 mutants lacked this regulatory activity. These results allowed the elucidation of a novel transcriptional autoregulatory mechanism of TDP-43. |
| 巻・号 | 11(1) |
| ページ | 8720 |
| 公開日 | 2021-4-22 |
| DOI | 10.1038/s41598-021-88015-y |
| PII | 10.1038/s41598-021-88015-y |
| PMID | 33888768 |
| PMC | PMC8062691 |
| MeSH | Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / physiopathology Base Sequence DNA-Binding Proteins / genetics* HEK293 Cells Humans Introns* Motor Neurons / physiology Promoter Regions, Genetic* |
| IF | 3.998 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 201B7(HPS0063) |