The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.
Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2delta B delta M). We show that the level of telomere dysfunction correlates with the level of TRF2delta B delta M protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2delta B delta M expression. Apoptosis was associated with higher expression of TRF2delta B delta M, whereas cellular senescence was associated with low levels of TRF2delta B delta M) expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.
Lechel
André
A
Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Satyanarayana
Ande
A
Ju
Zhenyu
Z
Plentz
Ruben R
RR
Schaetzlein
Sonja
S
Rudolph
Cornelia
C
Wilkens
Ludwig
L
Wiemann
Stephanie U
SU
Saretzki
Gabriele
G
Malek
Nisar P
NP
Manns
Michael P
MP
Buer
Jan
J
Rudolph
K Lenhard
KL
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53
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