title: Myt3 suppression sensitizes islet cells to high glucose-induced cell death via Bim induction.
abstract: Diabetes is a chronic disease that results from the body's inability to properly control circulating blood glucose levels. The loss of glucose homoeostasis can arise from a loss of β-cell mass because of immune-cell-mediated attack, as in type 1 diabetes, and/or from dysfunction of individual β-cells (in conjunction with target organ insulin resistance), as in type 2 diabetes. A better understanding of the transcriptional pathways regulating islet-cell survival is of great importance for the development of therapeutic strategies that target β-cells for diabetes. To this end, we previously identified the transcription factor Myt3 as a pro-survival factor in islets following acute suppression of Myt3 in vitro. To determine the effects of Myt3 suppression on islet-cell survival in vivo, we used an adenovirus to express an shRNA targeting Myt3 in syngeneic optimal and marginal mass islet transplants, and demonstrate that suppression of Myt3 impairs the function of marginal mass grafts. Analysis of grafts 5 weeks post-transplant revealed that grafts transduced with the shMyt3 adenovirus contained ~20% the number of transduced cells as grafts transduced with a control adenovirus. In fact, increased apoptosis and significant cell loss in the shMyt3-transduced grafts was evident after only 5 days, suggesting that Myt3 suppression sensitizes islet cells to stresses present in the early post-transplant period. Specifically, we find that Myt3 suppression sensitizes islet cells to high glucose-induced cell death via upregulation of the pro-apoptotic Bcl2 family member Bim. Taken together these data suggest that Myt3 may be an important link between glucotoxic and immune signalling pathways.
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: B R
authors.initials: BR
authors.lastname: Tennant
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: B
authors.initials: B
authors.lastname: Vanderkruk
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: J
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: D
authors.initials: D
authors.lastname: Dai
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.|Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5.
authors.forename: C B
authors.initials: CB
authors.lastname: Verchere
authors.affiliation: Child and Family Research Institute, British Columbia Children's Hospital, 950 W28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.|Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: B G
authors.initials: BG
authors.lastname: Hoffman
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000072224:Bcl-2-Like Protein 11 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin; D016019:Survival Analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014185:Transplantation, Isogeneic
chemical_list: D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C581556:Myt3 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D013311:Streptozocin; D005947:Glucose