دورية أكاديمية
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BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells.

التفاصيل البيبلوغرافية
العنوان: BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells.
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.
References: Teo, A. K., Wagers, A. J. & Kulkarni, R. N. New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism. Cell Metab. 18, 775–791 (2013). (PMID: 10.1016/j.cmet.2013.08.010)
Loo, L. S. W., Lau, H. H., Jasmen, J. B., Lim, C. S. & Teo, A. K. K. An arduous journey from human pluripotent stem cells to functional pancreatic beta cells. Diabetes Obes. Metab. 20, 3–13 (2018). (PMID: 10.1111/dom.12996)
TeSlaa, T., Setoguchi, K. & Teitell, M. A. Mitochondria in human pluripotent stem cell apoptosis. Semin Cell Dev. Biol. 52, 76–83 (2016). (PMID: 10.1016/j.semcdb.2016.01.027)
Wang, E. S. et al. Fas-activated mitochondrial apoptosis culls stalled embryonic stem cells to promote differentiation. Curr. Biol. 25, 3110–3118 (2015). (PMID: 10.1016/j.cub.2015.10.020)
Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011). (PMID: 10.1016/j.cell.2011.10.033)
Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326 (1998). (PMID: 10.1126/science.281.5381.1322)
Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001). (PMID: 10.1126/science.1059108)
Opferman, J. T. & Kothari, A. Anti-apoptotic BCL-2 family members in development. Cell Death Differ. 25, 37–45 (2018). (PMID: 10.1038/cdd.2017.170)
Ardehali, R. et al. Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors. Proc. Natl Acad. Sci. USA 108, 3282–3287 (2011). (PMID: 10.1073/pnas.1019047108)
Dumitru, R. et al. Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis. Mol. Cell 46, 573–583 (2012). (PMID: 10.1016/j.molcel.2012.04.002)
Teo, A. K. et al. Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia. Stem Cell Rep. 6, 357–367 (2016). (PMID: 10.1016/j.stemcr.2016.01.007)
Teo, A. K. et al. PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells. Stem Cell Rep. 4, 578–590 (2015). (PMID: 10.1016/j.stemcr.2015.02.015)
Lessene, G. et al. Structure-guided design of a selective BCL-X(L) inhibitor. Nat. Chem. Biol. 9, 390–397 (2013). (PMID: 10.1038/nchembio.1246)
Heller, R. S. et al. Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation. Dev. Dyn. 225, 260–270 (2002). (PMID: 10.1002/dvdy.10157)
Papadopoulou, S. & Edlund, H. Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes 54, 2844–2851 (2005). (PMID: 10.2337/diabetes.54.10.2844)
Li, Y. et al. Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev. 22, 3050–3063 (2008). (PMID: 10.1101/gad.1687308)
Stuckenholz, C. et al. Sfrp5 modulates both Wnt and BMP signaling and regulates gastrointestinal organogenesis [corrected] in the zebrafish, Danio rerio. PLoS ONE 8, e62470 (2013). (PMID: 10.1371/journal.pone.0062470)
Pagliuca, F. W. et al. Generation of functional human pancreatic beta cells in vitro. Cell 159, 428–439 (2014). (PMID: 10.1016/j.cell.2014.09.040)
Matsuzaki, Y. et al. Role of bcl-2 in the development of lymphoid cells from the hematopoietic stem cell. Blood 89, 853–862 (1997). (PMID: 10.1182/blood.V89.3.853)
Kamada, S. et al. bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res. 55, 354–359 (1995). (PMID: 7812968)
Michaelidis, T. M. et al. Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17, 75–89 (1996). (PMID: 10.1016/S0896-6273(00)80282-2)
Savitt, J. M., Jang, S. S., Mu, W., Dawson, V. L. & Dawson, T. M. Bcl-x is required for proper development of the mouse substantia nigra. J. Neurosci. 25, 6721–6728 (2005). (PMID: 10.1523/JNEUROSCI.0760-05.2005)
Carrington, E. M. et al. Islet beta-cells deficient in Bcl-xL develop but are abnormally sensitive to apoptotic stimuli. Diabetes 58, 2316–2323 (2009). (PMID: 10.2337/db08-1602)
Alavian, K. N. et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat. Cell Biol. 13, 1224–1233 (2011). (PMID: 10.1038/ncb2330)
Sung, K. F. et al. Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis. Exp. Cell Res. 315, 1975–1989 (2009). (PMID: 10.1016/j.yexcr.2009.01.009)
Lindenboim, L., Kringel, S., Braun, T., Borner, C. & Stein, R. Bak but not Bax is essential for Bcl-xS-induced apoptosis. Cell Death Differ. 12, 713–723 (2005). (PMID: 10.1038/sj.cdd.4401638)
Brooks, C. et al. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc. Natl Acad. Sci. USA 104, 11649–11654 (2007). (PMID: 10.1073/pnas.0703976104)
Willis, S. N. et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 19, 1294–1305 (2005). (PMID: 10.1101/gad.1304105)
Sattler, M. et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983–986 (1997). (PMID: 10.1126/science.275.5302.983)
Ito, K. & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256 (2014). (PMID: 10.1038/nrm3772)
Chen, Y. B. et al. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J. Cell Biol. 195, 263–276 (2011). (PMID: 10.1083/jcb.201108059)
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
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-020-2589-7