التفاصيل البيبلوغرافية
| العنوان: |
An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation |
| المؤلفون: |
Saarimaki-Vire, Jonna, Balboa, Diego, Russell, Mark A., Saarikettu, Juha, Kinnunen, Matias, Keskitalo, Salla, Malhi, Amrinder, Valensisi, Cristina, Andrus, Colin, Eurola, Solja, Grym, Heli, Ustinov, Jarkko, Wartiovaara, Kirmo, Hawkins, R. David, Silvennoinen, Olli, Varjosalo, Markku, Morgan, Noel G., Otonkoski, Timo |
| المساهمون: |
Research Programs Unit, Research Programme for Molecular Neurology, Institute of Biotechnology, HUSLAB, Clinicum, Molecular Systems Biology, Timo Pyry Juhani Otonkoski / Principal Investigator, Children's Hospital, Lastentautien yksikkö, HUS Children and Adolescents |
| بيانات النشر: |
Cell Press |
| سنة النشر: |
2017 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
PLURIPOTENT STEM-CELLS, BETA-LIKE CELLS, IN-VITRO, ENDOCRINE PANCREAS, PROGENITOR CELLS, KNOCKOUT MICE, GENERATION, NEUROGENIN3, EXPRESSION, REVEALS, 3111 Biomedicine, 1182 Biochemistry, cell and molecular biology |
| الوصف: |
Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3(K392R,) on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3(K392R) and healthy-control cells, but in later stages, NEUROG3 expressionwas upregulated prematurely in STAT3(K392R) cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3(K392R) -activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3(K392R). Collectively, our results demonstrate that the STAT3(K392R) mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression. ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
Anni Laitinen, Eila Korhonen, HazemIbrahim, Vaino Lithovius, NooraAarnio, Jessica Chaffey, and Niina Siiskonen are thanked for their professional technical assistance. Wethank Elena Senis (Vall d'Hebron Institute of Oncology) for advice on T7 endonuclease assay. We are grateful to Ras Trokovic and Milla Mikkola for providing iPSC (HEL72.1, HEL72A, and HEL72D) lines. D.B. is a member of the Doctoral School of Health Sciences at University of Helsinki. This project was funded by the Academy of Finland (grant number 257157) Sigrid Juselius Foundation, Novo Nordisk Foundation (grant numbers NNF16OC0021090, NNF15OC0016426, NNF14OC0010719, and NNF13OC0005565), the EU 7FP Integrated project BETACURE, the Diabetes Research Foundation, and Diabetes UK.; Saarimaki-Vire , J , Balboa , D , Russell , M A , Saarikettu , J , Kinnunen , M , Keskitalo , S , Malhi , A , Valensisi , C , Andrus , C , Eurola , S , Grym , H , Ustinov , J , Wartiovaara , K , Hawkins , R D , Silvennoinen , O , Varjosalo , M , Morgan , N G & Otonkoski , T 2017 , ' An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation ' , Cell Reports , vol. 19 , no. 2 , pp. 281-294 . https://doi.org/10.1016/j.celrep.2017.03.055Test; ORCID: /0000-0002-1340-9732/work/37568866; ORCID: /0000-0001-5555-1975/work/45024037; 85017320165; 376d681d-b621-4997-b443-ad0fdf873b3e; http://hdl.handle.net/10138/189045Test; 000401132600006 |
| الإتاحة: |
http://hdl.handle.net/10138/189045Test |
| حقوق: |
cc_by_nc_nd ; openAccess ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: |
edsbas.F8CA4BC8 |
| قاعدة البيانات: |
BASE |
