The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation

Hseyin Sirma, Mukesh Kumar, Jitendra K. Meena, Britta Witt, Julia M. Weise, Andre Lechel, Satyanarayana Ande, Vadim Sakk, Christiane Guguenguillouzo, Lars Zender, Karllenhard Rudolph, Cagatay Gnes

Research output: Contribution to journalArticle

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Abstract

Background & Aims: 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.

Original languageEnglish (US)
Pages (from-to)326-337.e3
JournalGastroenterology
Volume141
Issue number1
DOIs
StatePublished - Jul 2011

Fingerprint

Liver Regeneration
Telomerase
Hepatocytes
E2F7 Transcription Factor
Liver
Hepatectomy
Human Activities
human TERT protein
Transgenic Mice
Biopsy
Cell Line
Wounds and Injuries
Growth

Keywords

  • Chromosome
  • Hepatitis
  • Liver Disease
  • Telomere

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation. / Sirma, Hseyin; Kumar, Mukesh; Meena, Jitendra K.; Witt, Britta; Weise, Julia M.; Lechel, Andre; Ande, Satyanarayana; Sakk, Vadim; Guguenguillouzo, Christiane; Zender, Lars; Rudolph, Karllenhard; Gnes, Cagatay.

In: Gastroenterology, Vol. 141, No. 1, 07.2011, p. 326-337.e3.

Research output: Contribution to journalArticle

Sirma, H, Kumar, M, Meena, JK, Witt, B, Weise, JM, Lechel, A, Ande, S, Sakk, V, Guguenguillouzo, C, Zender, L, Rudolph, K & Gnes, C 2011, 'The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation', Gastroenterology, vol. 141, no. 1, pp. 326-337.e3. https://doi.org/10.1053/j.gastro.2011.03.047
Sirma, Hseyin ; Kumar, Mukesh ; Meena, Jitendra K. ; Witt, Britta ; Weise, Julia M. ; Lechel, Andre ; Ande, Satyanarayana ; Sakk, Vadim ; Guguenguillouzo, Christiane ; Zender, Lars ; Rudolph, Karllenhard ; Gnes, Cagatay. / The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation. In: Gastroenterology. 2011 ; Vol. 141, No. 1. pp. 326-337.e3.
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AU - Kumar, Mukesh

AU - Meena, Jitendra K.

AU - Witt, Britta

AU - Weise, Julia M.

AU - Lechel, Andre

AU - Ande, Satyanarayana

AU - Sakk, Vadim

AU - Guguenguillouzo, Christiane

AU - Zender, Lars

AU - Rudolph, Karllenhard

AU - Gnes, Cagatay

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N2 - Background & Aims: 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.

AB - Background & Aims: 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.

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KW - Telomere

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