title: Foxa2 may modulate hepatic apoptosis through the cIAP1 pathway.
abstract: Hepatocyte apoptosis is a ubiquitous feature of chronic liver injury, but the molecular mechanism remains to be determined. The liver-enriched Foxa2 transcription factor has been implicated in inflammation and neoplasia. Foxa2 may play a role in the regulation of apoptosis. This study aimed to investigate the relationship between Foxa2 and hepatic apoptosis. Apoptosis was induced with different causative factors as measured by caspase activity and TUNEL assay. Results showed that the apoptotic injury was associated with a downregulation of Foxa2. Foxa2-expressing vectors decreased apoptosis, whereas siRNA silencing of Foxa2 increased apoptosis in HepG2 cells. Foxa2 was correlated with expression profiling of anti-apoptotic genes cIAP1, cIAP2, XIAP, and survivin. Significantly, the cIAP1 expression was decreased by siRNA silencing of Foxa2, but increased by Foxa2-expressing vectors. The promoter of cIAP1 had specific DNA sequences that could be bound by Foxa2 nuclear protein as demonstrated by EMSA and gel supershift assay. The cIAP1 promoter was also occupied by Foxa2 nuclear factor through ChIP assay. Deletion of putative Foxa2 binding domains in cIAP1 promoter significantly reduced its promoter activity.
  
  
  CONCLUSIONS
  A mechanism by which Foxa2 transcription factor modulates hepatic apoptosis may be through cIAP1 signaling pathway. Foxa2 can be a potential target for therapeutic intervention in liver diseases.
authors.affiliation: Departments of Surgery, University of Illinois College of Medicine at Peoria, IL 61605, USA. kewang@uic.edu
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.forename: John J
authors.initials: JJ
authors.lastname: Brems
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.forename: Ai-Xuan
authors.initials: AX
authors.lastname: Holterman
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D056945:Hep G2 Cells; D051542:Hepatocyte Nuclear Factor 3-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; C496502:FOXA2 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; D051542:Hepatocyte Nuclear Factor 3-beta