title: Ets-1 as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells.
abstract: Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic β-cell failure in type 2 diabetes. Pancreatic β-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to β-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of β-cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic β-cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: N
authors.initials: N
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: D-C
authors.initials: DC
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: X
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050784:Proto-Oncogene Protein c-ets-1