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ID 62455
Author
Fukui, Yuko Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University
Hayano, Satoru Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University ORCID Kaken ID researchmap
Kawanabe, Noriaki Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Kaken ID publons
Wang, Ziyi Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University
Shimada, Akira Department of Pediatric Hematology/Oncology Okayama University Hospital ORCID Kaken ID researchmap
Saito, Megumu K. Department of Clinical Application, Center for iPS Cell Research and Application Kyoto University
Asaka, Isao Department of Fundamental Cell Technology, Center for iPS Cell Research and Application Kyoto University
Kamioka, Hiroshi Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Kaken ID publons researchmap
Abstract
Diamond-Blackfan anemia (DBA) is a genetic disorder caused by mutations in genes encoding ribosomal proteins and characterized by erythroid aplasia and various physical abnormalities. Although accumulating evidence suggests that defective ribosome biogenesis leads to p53-mediated apoptosis in erythroid progenitor cells, little is known regarding the underlying causes of the physical abnormalities. In this study, we established induced pluripotent stem cells from a DBA patient with RPL5 haploinsufficiency. These cells retained the ability to differentiate into osteoblasts and chondrocytes. However, RPL5 haploinsufficiency impaired the production of mucins and increased apoptosis in differentiated chondrocytes. Increased expression of the pro-apoptotic genes BAX and CASP9 further indicated that RPL5 haploinsufficiency triggered p53-mediated apoptosis in chondrocytes. MDM2, the primary negative regulator of p53, plays a crucial role in erythroid aplasia in DBA patient. We found the phosphorylation level of MDM2 was significantly decreased in RPL5 haploinsufficient chondrocytes. In stark contrast, we found no evidence that RPL5 haploinsufficiency impaired osteogenesis. Collectively, our data support a model in which RPL5 haploinsufficiency specifically induces p53-mediated apoptosis in chondrocytes through MDM2 inhibition, which leads to physical abnormalities in DBA patients.
Keywords
iPS cell
RPL5
cleft lip and palate
chondrocyte
Diamond-Blackfan Anemia
Note
This is an Accepted Manuscript of an article published by Wiley.
This fulltext is available in Sep. 2022.
This is the peer reviewed version of the following article: [Fukui, Y, Hayano, S, Kawanabe, N, Wang, Z, Shimada, A, Saito, MK, et al. Investigation of the molecular causes underlying physical abnormalities in Diamond-Blackfan anemia patients with RPL5 haploinsufficiency. Pathology International. 2021; 1-11. https://doi.org/10.1111/pin.13168], which has been published in final form at [https://doi.org/10.1111/pin.13168]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-ArchivedVersions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wileyor by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked toWiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof bythird parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Published Date
2021-9-29
Publication Title
Pathology International
Volume
volume2021
Publisher
Wiley
Start Page
1
End Page
11
ISSN
1320-5463
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
File Version
author
DOI
Related Url
isVersionOf https://doi.org/10.1111/pin.13168
Citation
Fukui, Y, Hayano, S, Kawanabe, N, Wang, Z, Shimada, A, Saito, MK, et al. Investigation of the molecular causes underlying physical abnormalities in Diamond-Blackfan anemia patients with RPL5 haploinsufficiency. Pathology International. 2021; 1-11. https://doi.org/10.1111/pin.13168
Funder Name
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science
助成番号
17935423
17K17323
18H09832
19H10381
19J11906