دورية أكاديمية
BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells.
العنوان: | BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells. |
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المؤلفون: | Loo LSW; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore., Soetedjo AAP; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore., Lau HH; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore., Ng NHJ; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore., Ghosh S; Computational and Statistical Systems Biology, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore., Nguyen L; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore., Krishnan VG; Molecular Engineering Lab, Proteos, Singapore, 138673, Singapore., Choi H; Computational and Statistical Systems Biology, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore., Roca X; School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore., Hoon S; Molecular Engineering Lab, Proteos, Singapore, 138673, Singapore., Teo AKK; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore, 138673, Singapore. drainteo@gmail.com.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore. drainteo@gmail.com.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore. drainteo@gmail.com. |
المصدر: | Cell death & disease [Cell Death Dis] 2020 May 18; Vol. 11 (5), pp. 378. Date of Electronic Publication: 2020 May 18. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Nature Pub. Group |
مواضيع طبية MeSH: | Apoptosis/*physiology , Pluripotent Stem Cells/*cytology , Proto-Oncogene Proteins c-bcl-2/*metabolism , bcl-X Protein/*metabolism, Caspase 3/metabolism ; Cell Differentiation/physiology ; Cell Proliferation/physiology ; Humans ; Pancreatic Neoplasms/metabolism ; Pluripotent Stem Cells/metabolism |
مستخلص: | The differentiation of human pluripotent stem cells into pancreatic cells involves cellular proliferation and apoptosis during cell fate transitions. However, their implications for establishing cellular identity are unclear. Here, we profiled the expression of BCL-2 family of proteins during pancreatic specification and observed an upregulation of BCL-xL, downregulation of BAK and corresponding downregulation of cleaved CASP3 representative of apoptosis. Experimental inhibition of BCL-xL reciprocally increased apoptosis and resulted in a decreased gene expression of pancreatic markers despite a compensatory increase in anti-apoptotic protein BCL-2. RNA-Seq analyses then revealed a downregulation of multiple metabolic genes upon inhibition of BCL-xL. Follow-up bioenergetics assays revealed broad downregulation of both glycolysis and oxidative phosphorylation when BCL-xL was inhibited. Early perturbation of BCL-xL during pancreatic specification also had subsequent detrimental effects on the formation of INS + pancreatic beta-like cells. In conclusion, the more differentiated pancreatic progenitors are dependent on anti-apoptotic BCL-xL for survival, whereas the less differentiated pancreatic progenitors that survived after WEHI-539 treatment would exhibit a more immature phenotype. Therefore, modulation of the expression level of BCL-xL can potentially increase the survival and robustness of pancreatic progenitors that ultimately define human pancreatic beta cell mass and function. |
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المشرفين على المادة: | 0 (BCL2 protein, human) 0 (BCL2L1 protein, human) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (bcl-X Protein) EC 3.4.22.- (CASP3 protein, human) EC 3.4.22.- (Caspase 3) |
تواريخ الأحداث: | Date Created: 20200520 Date Completed: 20210407 Latest Revision: 20210518 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC7235254 |
DOI: | 10.1038/s41419-020-2589-7 |
PMID: | 32424151 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2041-4889 |
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DOI: | 10.1038/s41419-020-2589-7 |