The Cellular Level of Telomere Dysfunction Determines Induction of Senescence or Apoptosis in Vivo

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2005 Feb 22

PMID 15723042

Citations 28

Authors

Andre Lechel

Ande Satyanarayana

Zhenyu Ju

Ruben R Plentz

Sonja Schaetzlein

Cornelia Rudolph

Ludwig Wilkens

Stephanie U Wiemann

Gabriele Saretzki

Nisar P Malek

Michael P Manns

Jan Buer

K Lenhard Rudolph

Affiliations

Soon will be listed here.

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.

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References

van Steensel B, Smogorzewska A, de Lange T . TRF2 protects human telomeres from end-to-end fusions. Cell. 1998; 92(3):401-13. DOI: 10.1016/s0092-8674(00)80932-0. View

Satyanarayana A, Manns M, Rudolph K . Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology. 2004; 40(2):276-83. DOI: 10.1002/hep.20308. View

Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T . p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999; 283(5406):1321-5. DOI: 10.1126/science.283.5406.1321. View

Chin L, Artandi S, Shen Q, Tam A, Lee S, Gottlieb G . p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999; 97(4):527-38. DOI: 10.1016/s0092-8674(00)80762-x. View

Krishnamurthy J, Torrice C, Ramsey M, Kovalev G, Al-Regaiey K, Su L . Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114(9):1299-307. PMC: 524230. DOI: 10.1172/JCI22475. View

Rudolph K, Chang S, Millard M, Schreiber-Agus N, DePinho R . Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science. 2000; 287(5456):1253-8. DOI: 10.1126/science.287.5456.1253. View

Pascale E, Battiloro E, Starace G, Verna R, DAmbrosio E . The length of telomeric G-rich strand 3'-overhang measured by oligonucleotide ligation assay. Nucleic Acids Res. 2001; 29(7):E35. PMC: 31296. DOI: 10.1093/nar/29.7.e35. View

de Lange T . Protection of mammalian telomeres. Oncogene. 2002; 21(4):532-40. DOI: 10.1038/sj.onc.1205080. View

Karlseder J, Smogorzewska A, de Lange T . Senescence induced by altered telomere state, not telomere loss. Science. 2002; 295(5564):2446-9. DOI: 10.1126/science.1069523. View

10.

Smogorzewska A, de Lange T . Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002; 21(16):4338-48. PMC: 126171. DOI: 10.1093/emboj/cdf433. View

11.

Gorbunova V, Seluanov A, Pereira-Smith O . Evidence that high telomerase activity may induce a senescent-like growth arrest in human fibroblasts. J Biol Chem. 2002; 278(9):7692-8. DOI: 10.1074/jbc.M212944200. View

12.

Blackburn E, Chan S, Chang J, Fulton T, Krauskopf A, McEachern M . Molecular manifestations and molecular determinants of telomere capping. Cold Spring Harb Symp Quant Biol. 2003; 65:253-63. DOI: 10.1101/sqb.2000.65.253. View

13.

Djojosubroto M, Choi Y, Lee H, Rudolph K . Telomeres and telomerase in aging, regeneration and cancer. Mol Cells. 2003; 15(2):164-75. View

14.

Satyanarayana A, Wiemann S, Buer J, Lauber J, Dittmar K, Wustefeld T . Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells. EMBO J. 2003; 22(15):4003-13. PMC: 169040. DOI: 10.1093/emboj/cdg367. View

15.

Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J . Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003; 5(8):741-7. PMC: 4940195. DOI: 10.1038/ncb1024. View

16.

Shay J, Wright W . A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res. 1991; 196(1):33-9. DOI: 10.1016/0014-4827(91)90453-2. View

17.

Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C . A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-7. PMC: 40985. DOI: 10.1073/pnas.92.20.9363. View

18.

dAdda di Fagagna F, Reaper P, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T . A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426(6963):194-8. DOI: 10.1038/nature02118. View

19.

Martin-Ruiz C, Saretzki G, Petrie J, Ladhoff J, Jeyapalan J, Wei W . Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span. J Biol Chem. 2004; 279(17):17826-33. DOI: 10.1074/jbc.M311980200. View

20.

Keys B, Serra V, Saretzki G, von Zglinicki T . Telomere shortening in human fibroblasts is not dependent on the size of the telomeric-3'-overhang. Aging Cell. 2004; 3(3):103-9. DOI: 10.1111/j.1474-9728.2004.00094.x. View