title: The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation.
abstract: OBJECTIVE
  Telomerase activity has not been detected in healthy human liver biopsy samples, but it is up-regulated in most human liver tumors. It is not clear whether telomerase is activated in response to acute or chronic liver injury. Telomerase activity is closely associated with expression of its catalytic subunit, telomerase reverse transcriptase (TERT). We analyzed the activity of the human TERT (hTERT) promoter during liver regeneration in vivo and hepatocyte proliferation in vitro.
  
  
  METHODS
  We used hTERTp-lacZ transgenic mice, which contain an 8.0-kilobase pair fragment of the hTERT gene promoter, to study the role of TERT in liver regeneration following partial hepatectomy. As an in vitro model, we used the HepaRG cell line as a new model system for human hepatocyte proliferation and differentiation.
  
  
  RESULTS
  Activity of the hTERT promoter increased significantly after partial hepatectomy; it was also induced in hepatocytes, based on immunohistologic analysis. Similar to the in vivo results, telomerase activity and hTERT expression were up-regulated in proliferating HepaRG cells and repressed in response to growth arrest and differentiation. Promoter mapping revealed that a proximal 0.3-kilobase pair fragment contains all elements necessary for regulation of hTERT in HepaRG cells. We identified E2F2 and E2F7 as transcription factors that control the differential expression of hTERT in proliferating hepatocytes, in vitro and in vivo.
  
  
  CONCLUSIONS
  hTERT is induced in hepatocytes during liver regeneration, indicating a functional role for telomerase in human liver.
authors: Heinrich-Pette-Institute, Hamburg, Germany.
authors: Hüseyin
authors: H
authors: Sirma
authors: Mukesh
authors: M
authors: Kumar
authors: Jitendra K
authors: JK
authors: Meena
authors: Britta
authors: B
authors: Witt
authors: Julia M
authors: JM
authors: Weise
authors: Andre
authors: A
authors: Lechel
authors: Satyanarayana
authors: S
authors: Ande
authors: Vadim
authors: V
authors: Sakk
authors: Christiane
authors: C
authors: Guguen-Guillouzo
authors: Lars
authors: L
authors: Zender
authors: Karl-Lenhard
authors: KL
authors: Rudolph
authors: Cagatay
authors: C
authors: Günes
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050703:E2F2 Transcription Factor / Q000378:metabolism; D050702:E2F7 Transcription Factor / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006498:Hepatectomy; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007763:Lac Operon; D008099:Liver / Q000201:enzymology* / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D050436:Regulatory Elements, Transcriptional; D016160:Retinoblastoma Protein / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation
chemical_list: D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D050702:E2F7 Transcription Factor; C481054:E2F7 protein, human; C484940:E2f2 protein, mouse; C479901:E2f7 protein, mouse; D016160:Retinoblastoma Protein; C509186:TERT protein, human; D019098:Telomerase