論文 - 詳細
| RRC ID | 76061 |
|---|---|
| 著者 | Singh R, Smit RB, Wang X, Wang C, Racher H, Hansen D. |
| タイトル | Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line. |
| ジャーナル | PLoS Genet |
| Abstract |
Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline. |
| 巻・号 | 17(9) |
| ページ | e1009687 |
| 公開日 | 2021-9-1 |
| DOI | 10.1371/journal.pgen.1009687 |
| PII | PGENETICS-D-21-00876 |
| PMID | 34555015 |
| PMC | PMC8491880 |
| MeSH | Animals Caenorhabditis elegans / genetics* Germ Cells* Helminth Proteins / metabolism* Mutation Neoplasms / metabolism* Neoplasms / pathology Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction |
| 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 | 7 |
| 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 | |
| 線虫 | tm2838 tm6098 |