Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome.
Autor: | Lagundžin D; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.; Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Hu WF; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Law HCH; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Krieger KL; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Qiao F; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Clement EJ; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Drincic AT; Department of Internal Medicine: Diabetes, Endocrinology and Metabolism, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Nedić O; Institute for the Application of Nuclear Energy, University of Belgrade, Banatska, Belgrade, Serbia., Naldrett MJ; Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska-Lincoln, Nebraska, United States of America., Alvarez S; Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska-Lincoln, Nebraska, United States of America., Woods NT; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. |
---|---|
Jazyk: | angličtina |
Zdroj: | PloS one [PLoS One] 2019 Aug 28; Vol. 14 (8), pp. e0220568. Date of Electronic Publication: 2019 Aug 28 (Print Publication: 2019). |
DOI: | 10.1371/journal.pone.0220568 |
Abstrakt: | Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucose-stimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients. Competing Interests: The authors declared that no competing interests exist. |
Databáze: | MEDLINE |
Externí odkaz: | |
Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |