title: Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice.
abstract: OBJECTIVE
  Prolactin (PRL)-stimulated beta cell proliferation is critical for maternal pancreatic beta cell mass expansion during pregnancy. However, the molecular effectors of the multiple putative signalling pathways downstream of the PRL receptor (PRL-R) are still elusive. Survivin has been shown to be induced during pregnancy. The aim of the present study was to define the essential role of survivin in gestational beta cell mass expansion.
  
  
  METHODS
  Expression of survivin was assessed in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated with PRL. Pregnant mice with targeted deletion of the survivin gene (also known as Birc5) in beta cells were assessed to determine the essential function of survivin in maternal beta cell mass expansion. INS-1 cells stimulated with PRL were used to explore the role of survivin in signalling pathways downstream of the PRL-R.
  
  
  RESULTS
  Survivin was significantly upregulated in maternal islets during pregnancy. With PRL stimulation, induction of survivin expression occurred predominantly in the nucleus and was associated with cell cycle progression to S and G2/M phase. Beta cell-specific survivin-knockout pregnant mice displayed glucose intolerance, attenuated beta cell mass expansion and impaired beta cell proliferation, with significant attenuation in the increased expression of Cdk4/Ccnd1, E2f1, p53 (also known as Trp53) and p21 (also known as Cdkn1a) compared with wild-type controls during pregnancy. Targeted deletion of survivin in INS-1 cells resulted in cell cycle disturbance with an arrest in G1/S phase after PRL stimulation. Inhibitors of Akt, signal transducer and activator of transcription 5 (STAT5), PIM or extracellular signal-regulated kinase (ERK), significantly decreased the expression of survivin in PRL-stimulated INS-1 cells.
  
  
  CONCLUSIONS
  Survivin directly participates in PRL-mediated beta cell proliferation via Akt, STAT5-PIM and ERK signalling pathways during pregnancy.
authors.affiliation: Department of Endocrinology, First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, People's Republic of China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Jiayu
authors.initials: J
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Houxia
authors.initials: H
authors.lastname: Shi
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007340:Insulinoma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000077022:Survivin; D011388:Prolactin; D005947:Glucose