title: Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin.
abstract: OBJECTIVE
  Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for beta-cells.
  
  
  METHODS
  We generated mice harboring a conditional deletion of survivin in pancreatic endocrine cells using mice with a Pax-6-Cre transgene promoter construct driving tissue-specific expression of Cre-recombinase in these cells. We performed metabolic studies and immunohistochemical analyses to determine the effects of a mono- and biallelic deletion of survivin.
  
  
  RESULTS
  Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age. Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones. Exogenous expression of survivin in mature beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.
  
  
  CONCLUSIONS
  Our findings implicate survivin in the maintenance of beta-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes.
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishimura
authors.forename: Deborah
authors.initials: D
authors.lastname: Devor-Henneman
authors.forename: Donna
authors.initials: D
authors.lastname: Kusewitt
authors.forename: Haijuan
authors.initials: H
authors.lastname: Wang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Holloway
authors.forename: Takehiko
authors.initials: T
authors.lastname: Dohi
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Altura
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005934:Glucagon / Q000378:metabolism; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins; D013004:Somatostatin / Q000378:metabolism; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D013004:Somatostatin; D005934:Glucagon