Human telomerase reverse transcriptase promoter is activated during liver regeneration and hepatocyte proliferation

Background & Aims. Telomerase activity is non-detectable in healthy human liver biopsies but it is up-regulated in most human liver cancers. There is an ongoing debate whether telomerase is activated in response to acute or chronic liver injury. Telomerase activity is closely attributable to the expression of its catalytic subunit telomerase reverse transcriptase (TERT). Here we analyzed the activity of the human TERT (hTERT) promoter during liver regeneration in vivo and hepatocyte proliferation in vitro. Methods. As an in vivo model we used the hTERTp-lacZ transgenic mice, which contain an 8.0 kbp fragment of the hTERT gene promoter. Liver regeneration was induced by 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. hTERT promoter activity showed a significant increase after partial hepatectomy. The hTERT promoter activity is induced in hepatocytes as shown by immunohistological 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. Moreover, we show that telomerase activity is essential for HepaRG proliferation. Promoter mapping revealed that a proximal 0.3 kbp fragment harbors all necessary elements for the regulation of hTERT gene in HepaRG cells. We further identified E2F2 and E2F7 as main factors governing the differential expression of hTERT gene in proliferating hepatocytes in vitro as well as in vivo. Conclusions. This is the first experimental evidence indicating that hTERT is induced in hepatocytes during liver regeneration. These data imply a pivotal functional role of telomerase activity in human liver.

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