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
リソース情報
ヒト・動物細胞 201B7(HPS0063)