DDR-mediated crosstalk between DNA-damaged cells and their microenvironment

Frontiers in Genetics

Volumn 5, Issue FEB, 2015, Pages

  Malaquin, Nicolas ^a   Carrier Leclerc, Audrey ^a   Dessureault, Mireille ^a   Rodier, Francis ^a,b  

^a Institut du Cancer de Montreal   (Canada)

^b UNIVERSITÉ DE MONTRÉAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; CHECKPOINT KINASE 2; COLLAGEN; DEATH RECEPTOR 5; FIBRONECTIN; GELATINASE A; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HISTONE H2AX; I KAPPA B KINASE ALPHA; I KAPPA B KINASE BETA; I KAPPA B KINASE GAMMA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 6; INTERLEUKIN 8; INTERSTITIAL COLLAGENASE; LAMININ; MITOGEN ACTIVATED PROTEIN KINASE P38; MONOCYTE CHEMOTACTIC PROTEIN 1; NATURAL KILLER CELL RECEPTOR NKG2D; NIBRIN; PROTEIN P21; PROTEIN P53; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; SOMATOMEDIN; STROMELYSIN; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG;

APOPTOSIS; ARTICLE; CELL COMMUNICATION; CELL DAMAGE; CELL SURVIVAL; CHRONIC INFLAMMATION; DNA DAMAGE; DNA REPAIR; GENE EXPRESSION; GENE MUTATION; GENOMIC INSTABILITY; GROWTH DISORDER; HUMAN; IMMUNE RESPONSE; NONHUMAN; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84923543492     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2015.00094     Document Type: Article

References (75)

1. Acosta, J.C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J.P., Athineos, D., Kang, T.W., Lasitschka, F., Andrulis, M., Pascual, G., Morris, K.J., Khan, S., Jin, H., Dharmalingam, G., Snijders, A.P., Carroll, T., Capper, D., Pritchard, C., Inman, G.J., Longerich, T., Sansom, O.J., Benitah, S.A., Zender, L., and Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15, 978-990. doi: 10.1038/ncb2784.
2. Acosta, J.C., and Gil, J. (2012). Senescence: a new weapon for cancer therapy. Trends Cell Biol 22, 211-219. doi: 10.1016/j.tcb.2011.11.006.
3. Acosta, J.C., O'loghlen, A., Banito, A., Guijarro, M.V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., Takatsu, Y., Melamed, J., D'adda Di Fagagna, F., Bernard, D., Hernando, E., and Gil, J. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006-1018. doi: 10.1016/j.cell.2008.03.038.
4. Azzam, E.I., De Toledo, S.M., Gooding, T., and Little, J.B. (1998). Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. Radiat Res 150, 497-504.
5. Azzam, E.I., De Toledo, S.M., and Little, J.B. (2001). Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha -particle irradiated to nonirradiated cells. Proc Natl Acad Sci U S A 98, 473-478. doi: 10.1073/pnas.011417098.
6. Azzam, E.I., De Toledo, S.M., and Little, J.B. (2003). Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect. Oncogene 22, 7050-7057. doi: 10.1038/sj.onc.1206961.
7. Azzam, E.I., De Toledo, S.M., Spitz, D.R., and Little, J.B. (2002). Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res 62, 5436-5442.
8. Baker, D.J., Wijshake, T., Tchkonia, T., Lebrasseur, N.K., Childs, B.G., Van De Sluis, B., Kirkland, J.L., and Van Deursen, J.M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232-236. doi: 10.1038/nature10600.
9. Bavik, C., Coleman, I., Dean, J.P., Knudsen, B., Plymate, S., and Nelson, P.S. (2006). The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res 66, 794-802. doi: 10.1158/0008-5472.CAN-05-1716.
10. Bonner, W.M., Redon, C.E., Dickey, J.S., Nakamura, A.J., Sedelnikova, O.A., Solier, S., and Pommier, Y. (2008). GammaH2AX and cancer. Nat Rev Cancer 8, 957-967. doi: 10.1038/nrc2523.
11. Burdak-Rothkamm, S., Rothkamm, K., and Prise, K.M. (2008). ATM acts downstream of ATR in the DNA damage response signaling of bystander cells. Cancer Res 68, 7059- 7065. doi: 10.1158/0008-5472.CAN-08-0545.
12. Burdak-Rothkamm, S., Short, S.C., Folkard, M., Rothkamm, K., and Prise, K.M. (2007). ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 26, 993-1002. doi: 10.1038/sj.onc.1209863.
13. Campisi, J. (2003). Cancer and ageing: rival demons? Nat Rev Cancer 3, 339-349. doi: 10.1038/nrc1073.
14. Campisi, J., and D'adda Di Fagagna, F. (2007). Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8, 729-740. doi: 10.1038/nrm2233.
15. Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J.E., Premsrirut, P., Luo, W., Chicas, A., Lee, C.S., Kogan, S.C., and Lowe, S.W. (2011). Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev 25, 2125-2136. doi: 10.1101/gad.17276711.
16. Coppe, J.P., Desprez, P.Y., Krtolica, A., and Campisi, J. (2010a). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5, 99-118. doi: 10.1146/annurev-pathol-121808-102144.
17. Coppe, J.P., Patil, C.K., Rodier, F., Krtolica, A., Beausejour, C.M., Parrinello, S., Hodgson, J.G., Chin, K., Desprez, P.Y., and Campisi, J. (2010b). A human-like senescenceassociated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS One 5, e9188. doi: 10.1371/journal.pone.0009188.
18. Coppe, J.P., Patil, C.K., Rodier, F., Sun, Y., Munoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.Y., and Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6, 2853-2868. doi: 10.1371/journal.pbio.0060301.
19. Coppe, J.P., Rodier, F., Patil, C.K., Freund, A., Desprez, P.Y., and Campisi, J. (2011). Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286, 36396-36403. doi: 10.1074/jbc.M111.257071.
20. D'adda Di Fagagna, F. (2008). Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8, 512-522. doi: 10.1038/nrc2440.
21. D'adda Di Fagagna, F., Reaper, P.M., Clay-Farrace, L., Fiegler, H., Carr, P., Von Zglinicki, T., Saretzki, G., Carter, N.P., and Jackson, S.P. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194-198. doi: 10.1038/nature02118.
22. Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.M., Vijg, J., Van Steeg, H., Dolle, M.E., Hoeijmakers, J.H., De Bruin, A., Hara, E., and Campisi, J. (2014). An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA. Dev Cell. doi: 10.1016/j.devcel.2014.11.012.
23. Dickey, J.S., Baird, B.J., Redon, C.E., Avdoshina, V., Palchik, G., Wu, J., Kondratyev, A., Bonner, W.M., and Martin, O.A. (2012). Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity. Nucleic Acids Res 40, 10274- 10286. doi: 10.1093/nar/gks795.
24. Dickey, J.S., Baird, B.J., Redon, C.E., Sokolov, M.V., Sedelnikova, O.A., and Bonner, W.M. (2009). Intercellular communication of cellular stress monitored by gamma-H2AX induction. Carcinogenesis 30, 1686-1695. doi: 10.1093/carcin/bgp192.
25. Finnberg, N., Gruber, J.J., Fei, P., Rudolph, D., Bric, A., Kim, S.H., Burns, T.F., Ajuha, H., Page, R., Wu, G.S., Chen, Y., Mckenna, W.G., Bernhard, E., Lowe, S., Mak, T., and El-Deiry, W.S. (2005). DR5 knockout mice are compromised in radiation-induced apoptosis. Mol Cell Biol 25, 2000-2013. doi: 10.1128/MCB.25.5.2000-2013.2005.
26. Freund, A., Patil, C.K., and Campisi, J. (2011). p38MAPK is a novel DNA damage responseindependent regulator of the senescence-associated secretory phenotype. EMBO J 30, 1536-1548. doi: 10.1038/emboj.2011.69.
27. Gasser, S., Orsulic, S., Brown, E.J., and Raulet, D.H. (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186- 1190. doi: 10.1038/nature03884.
28. Guo, Z., Kozlov, S., Lavin, M.F., Person, M.D., and Paull, T.T. (2010). ATM activation by oxidative stress. Science 330, 517-521. doi: 10.1126/science.1192912.
29. Hagelstrom, R.T., Askin, K.F., Williams, A.J., Ramaiah, L., Desaintes, C., Goodwin, E.H., Ullrich, R.L., and Bailey, S.M. (2008). DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals. Oncogene 27, 6761-6769. doi: 10.1038/onc.2008.276.
30. Harper, J.W., and Elledge, S.J. (2007). The DNA damage response: ten years after. Mol Cell 28, 739-745. doi: 10.1016/j.molcel.2007.11.015.
31. Havaki, S., Kotsinas, A., Chronopoulos, E., Kletsas, D., Georgakilas, A., and Gorgoulis, V.G. (2014). The role of oxidative DNA damage in radiation induced bystander effect. Cancer Lett. doi: 10.1016/j.canlet.2014.01.023.
32. Huang, T.T., Wuerzberger-Davis, S.M., Wu, Z.H., and Miyamoto, S. (2003). Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 115, 565-576.
33. Hubackova, S., Krejcikova, K., Bartek, J., and Hodny, Z. (2012). IL1- and TGFbeta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging (Albany NY) 4, 932-951.
34. Iannello, A., Thompson, T.W., Ardolino, M., Lowe, S.W., and Raulet, D.H. (2013). p53- dependent chemokine production by senescent tumor cells supports NKG2Ddependent tumor elimination by natural killer cells. J Exp Med 210, 2057-2069. doi: 10.1084/jem.20130783.
35. Iyer, R., Lehnert, B.E., and Svensson, R. (2000). Factors underlying the cell growth-related bystander responses to alpha particles. Cancer Res 60, 1290-1298.
36. Jackson, S.P., and Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature 461, 1071-1078. doi: 10.1038/nature08467.
37. Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., Iken, M., Vucur, M., Weiss, S., Heikenwalder, M., Khan, S., Gil, J., Bruder, D., Manns, M., Schirmacher, P., Tacke, F., Ott, M., Luedde, T., Longerich, T., Kubicka, S., and Zender, L. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547-551. doi: 10.1038/nature10599.
38. Kirshner, J., Jobling, M.F., Pajares, M.J., Ravani, S.A., Glick, A.B., Lavin, M.J., Koslov, S., Shiloh, Y., and Barcellos-Hoff, M.H. (2006). Inhibition of transforming growth factorbeta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res 66, 10861-10869. doi: 10.1158/0008-5472.CAN-06- 2565.
39. Klammer, H., Kadhim, M., and Iliakis, G. (2010). Evidence of an adaptive response targeting DNA nonhomologous end joining and its transmission to bystander cells. Cancer Res 70, 8498-8506. doi: 10.1158/0008-5472.CAN-10-1181.
40. Ko, M., Lao, X.Y., Kapadia, R., Elmore, E., and Redpath, J.L. (2006). Neoplastic transformation in vitro by low doses of ionizing radiation: role of adaptive response and bystander effects. Mutat Res 597, 11-17. doi: 10.1016/j.mrfmmm.2005.08.013.
41. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.Y., and Campisi, J. (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98, 12072-12077. doi: 10.1073/pnas.211053698.
42. Kuilman, T., Michaloglou, C., Vredeveld, L.C., Douma, S., Van Doorn, R., Desmet, C.J., Aarden, L.A., Mooi, W.J., and Peeper, D.S. (2008). Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019-1031. doi: 10.1016/j.cell.2008.03.039.
43. Laberge, R.M., Adler, D., Demaria, M., Mechtouf, N., Teachenor, R., Cardin, G.B., Desprez, P.Y., Campisi, J., and Rodier, F. (2013). Mitochondrial DNA damage induces apoptosis in senescent cells. Cell Death Dis 4, e727. doi: 10.1038/cddis.2013.199.
44. Lam, A.R., Le Bert, N., Ho, S.S., Shen, Y.J., Tang, M.L., Xiong, G.M., Croxford, J.L., Koo, C.X., Ishii, K.J., Akira, S., Raulet, D.H., and Gasser, S. (2014). RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res 74, 2193-2203. doi: 10.1158/0008-5472.CAN-13-1703.
45. Little, J.B., Azzam, E.I., De Toledo, S.M., and Nagasawa, H. (2002). Bystander effects: intercellular transmission of radiation damage signals. Radiat Prot Dosimetry 99, 159- 162.
46. Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The hallmarks of aging. Cell 153, 1194-1217. doi: 10.1016/j.cell.2013.05.039.
47. Malaquin, N., Vercamer, C., Bouali, F., Martien, S., Deruy, E., Wernert, N., Chwastyniak, M., Pinet, F., Abbadie, C., and Pourtier, A. (2013). Senescent fibroblasts enhance early skin carcinogenic events via a paracrine MMP-PAR-1 axis. PLoS One 8, e63607. doi: 10.1371/journal.pone.0063607.
48. Miyamoto, S. (2011). Nuclear initiated NF-kappaB signaling: NEMO and ATM take center stage. Cell Res 21, 116-130. doi: 10.1038/cr.2010.179.
49. Moiseeva, O., Mallette, F.A., Mukhopadhyay, U.K., Moores, A., and Ferbeyre, G. (2006). DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell 17, 1583-1592. doi: 10.1091/mbc.E05-09-0858.
50. Morgan, W.F. (2003). Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro. Radiat Res 159, 567-580.
51. Nagasawa, H., and Little, J.B. (1992). Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res 52, 6394-6396.
52. Nagasawa, H., and Little, J.B. (2002). Bystander effect for chromosomal aberrations induced in wild-type and repair deficient CHO cells by low fluences of alpha particles. Mutat Res 508, 121-129.
53. Nelson, G., Wordsworth, J., Wang, C., Jurk, D., Lawless, C., Martin-Ruiz, C., and Von Zglinicki, T. (2012). A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345-349. doi: 10.1111/j.1474-9726.2012.00795.x.
54. Ohanna, M., Giuliano, S., Bonet, C., Imbert, V., Hofman, V., Zangari, J., Bille, K., Robert, C., Bressac-De Paillerets, B., Hofman, P., Rocchi, S., Peyron, J.F., Lacour, J.P., Ballotti, R., and Bertolotto, C. (2011). Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). Genes Dev 25, 1245-1261. doi: 10.1101/gad.625811.
55. Perez-Mancera, P.A., Young, A.R., and Narita, M. (2014). Inside and out: the activities of senescence in cancer. Nat Rev Cancer 14, 547-558. doi: 10.1038/nrc3773.
56. Rodier, F., and Campisi, J. (2011). Four faces of cellular senescence. J Cell Biol 192, 547- 556. doi: 10.1083/jcb.201009094.
57. Rodier, F., Campisi, J., and Bhaumik, D. (2007). Two faces of p53: aging and tumor suppression. Nucleic Acids Res 35, 7475-7484. doi: 10.1093/nar/gkm744.
58. Rodier, F., Coppe, J.P., Patil, C.K., Hoeijmakers, W.A., Munoz, D.P., Raza, S.R., Freund, A., Campeau, E., Davalos, A.R., and Campisi, J. (2009). Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11, 973-979. doi: 10.1038/ncb1909.
59. Rodier, F., Munoz, D.P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppe, J.P., Campeau, E., Beausejour, C.M., Kim, S.H., Davalos, A.R., and Campisi, J. (2011). DNASCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 124, 68-81. doi: 10.1242/jcs.071340.
60. Rogakou, E.P., Boon, C., Redon, C., and Bonner, W.M. (1999). Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146, 905-916.
61. Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S., and Bonner, W.M. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273, 5858-5868.
62. Salminen, A., Kauppinen, A., and Kaarniranta, K. (2012). Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 24, 835-845. doi: 10.1016/j.cellsig.2011.12.006.
63. Sedelnikova, O.A., Nakamura, A., Kovalchuk, O., Koturbash, I., Mitchell, S.A., Marino, S.A., Brenner, D.J., and Bonner, W.M. (2007). DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models. Cancer Res 67, 4295-4302. doi: 10.1158/0008-5472.CAN-06-4442.
64. Senturk, S., Mumcuoglu, M., Gursoy-Yuzugullu, O., Cingoz, B., Akcali, K.C., and Ozturk, M. (2010). Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology 52, 966-974. doi: 10.1002/hep.23769.
65. Shao, C., Folkard, M., and Prise, K.M. (2008). Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells. Oncogene 27, 434-440. doi: 10.1038/sj.onc.1210653.
66. Sokolov, M.V., Dickey, J.S., Bonner, W.M., and Sedelnikova, O.A. (2007). gamma-H2AX in bystander cells: not just a radiation-triggered event, a cellular response to stress mediated by intercellular communication. Cell Cycle 6, 2210-2212.
67. Sokolov, M.V., Smilenov, L.B., Hall, E.J., Panyutin, I.G., Bonner, W.M., and Sedelnikova, O.A. (2005). Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts. Oncogene 24, 7257-7265. doi: 10.1038/sj.onc.1208886.
68. Stilmann, M., Hinz, M., Arslan, S.C., Zimmer, A., Schreiber, V., and Scheidereit, C. (2009). A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation. Mol Cell 36, 365-378. doi: 10.1016/j.molcel.2009.09.032.
69. Sun, Y., Campisi, J., Higano, C., Beer, T.M., Porter, P., Coleman, I., True, L., and Nelson, P.S. (2012). Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18, 1359-1368. doi: 10.1038/nm.2890.
70. Sun, Y., and Nelson, P.S. (2012). Molecular pathways: involving microenvironment damage responses in cancer therapy resistance. Clin Cancer Res 18, 4019-4025. doi: 10.1158/1078-0432.CCR-11-0768.
71. Tanaka, T., Halicka, H.D., Huang, X., Traganos, F., and Darzynkiewicz, Z. (2006). Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. Cell Cycle 5, 1940-1945.
72. Tchkonia, T., Zhu, Y., Van Deursen, J., Campisi, J., and Kirkland, J.L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123, 966-972. doi: 10.1172/JCI64098.
73. Wu, C.J., Conze, D.B., Li, T., Srinivasula, S.M., and Ashwell, J.D. (2006). Sensing of Lys 63- linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol 8, 398-406. doi: 10.1038/ncb1384.
74. Wu, G.S., Burns, T.F., Mcdonald, E.R., 3rd, Jiang, W., Meng, R., Krantz, I.D., Kao, G., Gan, D.D., Zhou, J.Y., Muschel, R., Hamilton, S.R., Spinner, N.B., Markowitz, S., Wu, G., and El-Deiry, W.S. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17, 141-143. doi: 10.1038/ng1097-141.
75. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon- Cardo, C., and Lowe, S.W. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656-660. doi: 10.1038/nature05529.