title: The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Ande
authors.initials: A
authors.lastname: Satyanarayana
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
authors.forename: Sonja
authors.initials: S
authors.lastname: Schaetzlein
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rudolph
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.forename: Stephanie U
authors.initials: SU
authors.lastname: Wiemann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Saretzki
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: 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
chemical_list: D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53
references.citation: Cell. 1998 Feb 6;92(3):401-13
references.pmid: 9476899
references.citation: Hepatology. 2004 Aug;40(2):276-83
references.pmid: 15368430
references.citation: Science. 1999 Feb 26;283(5406):1321-5
references.pmid: 10037601
references.citation: Cell. 1999 May 14;97(4):527-38
references.pmid: 10338216
references.citation: J Clin Invest. 2004 Nov;114(9):1299-307
references.pmid: 15520862
references.citation: Science. 2000 Feb 18;287(5456):1253-8
references.pmid: 10678830
references.citation: Nucleic Acids Res. 2001 Apr 1;29(7):E35
references.pmid: 11266570
references.citation: Oncogene. 2002 Jan 21;21(4):532-40
references.pmid: 11850778
references.citation: Science. 2002 Mar 29;295(5564):2446-9
references.pmid: 11923537
references.citation: EMBO J. 2002 Aug 15;21(16):4338-48
references.pmid: 12169636
references.citation: J Biol Chem. 2003 Feb 28;278(9):7692-8
references.pmid: 12496279
references.citation: Cold Spring Harb Symp Quant Biol. 2000;65:253-63
references.pmid: 12760039
references.citation: Mol Cells. 2003 Apr 30;15(2):164-75
references.pmid: 12803478
references.citation: EMBO J. 2003 Aug 1;22(15):4003-13
references.pmid: 12881434
references.citation: Nat Cell Biol. 2003 Aug;5(8):741-7
references.pmid: 12855956
references.citation: Exp Cell Res. 1991 Sep;196(1):33-9
references.pmid: 1652450
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7
references.pmid: 7568133
references.citation: Nature. 2003 Nov 13;426(6963):194-8
references.pmid: 14608368
references.citation: J Biol Chem. 2004 Apr 23;279(17):17826-33
references.pmid: 14963037
references.citation: Aging Cell. 2004 Jun;3(3):103-9
references.pmid: 15153178
references.citation: Mol Cell Biol. 2004 Jun;24(12):5459-74
references.pmid: 15169907
references.citation: Hepatology. 2004 Jul;40(1):80-6
references.pmid: 15239089
references.citation: Nature. 1998 Apr 9;392(6676):569-74
references.pmid: 9560153