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論文
タイトル
タイトル(英)
AMBRA1 p.Gln30Arg Mutation, Identified in a Cowden Syndrome Family, Exhibits Hyperproliferative Potential in hTERT-RPE1 Cells
参照URL
https://researchmap.jp/toyonatsume/published_papers/40077539
著者
著者(英)
Sundaramoorthy Revathidevi,Kazuyoshi Hosomichi,Toyoaki Natsume,Hirofumi Nakaoka,Naoko T. Fujito,Hisako Akatsuka,Takehito Sato,Arasambattu Kannan Munirajan,Ituro Inoue
担当区分
概要
概要(英)
Cowden syndrome (CS) is a rare autosomal dominant disorder associated with multiple hamartomatous and neoplastic lesions in various organs. Most CS patients have been found to have germline mutations in the PTEN tumor suppressor. In the present study, we investigated the causative gene of CS in a family of PTEN (phosphatase and tensin homolog deleted on chromosome 10) -negative CS patients. Whole exome sequencing analysis revealed AMBRA1 (Autophagy and Beclin 1 Regulator 1) as a novel candidate gene harboring two germline variants: p.Gln30Arg (Q30R) and p.Arg1195Ser (R1195S). AMBRA1 is a key regulator of the autophagy signaling network and a tumor suppressor. To functionally validate the role of AMBRA1 in the clinical manifestations of CS, we generated AMBRA1 depletion and Q30R mutation in hTERT-RPE1 (humanTelomerase Reverse Transcriptase-immortalized Retinal Pigmented Epithelial cells) using the CRISPR-Cas9 gene editing system. We observed that both AMBRA1-depleted and mutant cells showed accumulation in the S phase, leading to hyperproliferation, which is a characteristic of hamartomatous lesions. Specifically, the AMBRA1 Q30R mutation disturbed the G1/S transition of cells, leading to continuous mitotic entry of mutant cells, irrespective of the extracellular condition. From our analysis of primary ciliogenesis in these cells, we speculated that the mitotic entry of AMBRA1 Q30R mutants could be due to non-functional primary cilia that lead to impaired processing of extracellular sensory signals. Additionally, we observed a situs inversus phenotype in ambra1-depleted zebrafish, a developmental abnormality resulting from dysregulated primary ciliogenesis. Taken together, we established that the AMBRA1 Q30R mutation that we observed in CS patients might play an important role in inducing the hyperproliferative potential of cells through regulating primary ciliogenesis.
出版者・発行元
出版者・発行元(英)
MDPI AG
誌名
誌名(英)
International Journal of Molecular Sciences
23
19
開始ページ
11124
終了ページ
11124
出版年月
2022年9月22日
査読の有無
査読有り
招待の有無
掲載種別
研究論文(学術雑誌)
ISSN
DOI URL
https://doi.org/10.3390/ijms231911124
共同研究・競争的資金等の研究課題
研究者
夏目 豊彰 (ナツメ トヨアキ)