International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Lechel, A
Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover

Co-Authors: Ande S, Rudolph KL
Institutions: Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover

Telomeres are specialised nucleo-protein structures at the end of eukaryotic chromosomes and the telomeric binding factor 2 (TRF2) is essential for the stabilization of the tertiary telomere structure. To characterize the consequences of telomere dysfunction in vivo we use two experimnetal systems: 1. Telomerase deficient mice lack the RNA component of telomerase (mTERC-/-) and show critical telomere shortening in late generations, 2. Expression of a dominant negative form of TRF2 (TRF2ΔBΔM ) induces rapid induction of telomere dysfunction in murine and human cells and was applied to mice by adenoviral transfer. Our studies in mTERC-/- mice show that telomere shortening is heterogeneous within an organ system and that a sub-population of cells with critically short telomeres is completely inhibited from entering the cell cycle. In contrast, cells with sufficient telomere reserves normally enter the cell cycle and compensate for organ regeneration by additional rounds of cell division. The cells with short telomeres that are blocked from organ regeneration have markers of cellular senescence. Our studies show that cellular senescence induced by telomere shortening is a conditionally active programme dependent on mitogen stimulation, in part mediated through the activation of MEK/MAPK-pathway. Expression of TRF2ΔBΔM triggered an apoptotic response in resting liver cells and a regenerative response in remnant liver cells which showed high rates of anaphase bridges - a sign of telomere dysfunction. Induction of apoptosis by inhibition of TRF2 was p53-independent, but cell cycle dependent and was prevented in regenerating liver cells during S- and G2/M phase. Our data show that the effects of telomere dysfunction can analyzed in different mouse models, which should allow to explore its role in regeneration and carcinogenesis.

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