Senescent Keratinocytes Die by Autophagic Programmed Cell Death

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2009 Jan 17

PMID 19147823

Citations 44

Authors

Karo Gosselin

Emeric Deruy

Sebastien Martien

Chantal Vercamer

Fatima Bouali

Thibault Dujardin

Christian Slomianny

Ludivine Houel-Renault

Fazia Chelli

Yvan de Launoit

Corinne Abbadie

Affiliations

Soon will be listed here.

Abstract

Normal cells reach senescence after a specific time and number of divisions, leading ultimately to cell death. Although escape from this fate may be a requisite step in neoplastic transformation, the mechanisms governing senescent cell death have not been well investigated. We show here, using normal human epidermal keratinocytes, that no apoptotic markers appear with senescence. In contrast, the expression of several proteins involved in the regulation of macroautophagy, notably Beclin-1 and Bcl-2, was found to change with senescence. The corpses occurring at the senescence growth plateau displayed a large central area delimited by the cytokeratin network that contained a huge quantity of autophagic vacuoles, the damaged nucleus, and most mitochondria. 3-methyladenine, an inhibitor of autophagosome formation, but not the caspase inhibitor zVAD, prevented senescent cell death. We conclude that senescent cells do not die by apoptosis, but as a result of high macroautophagic activity that targets the primary vital cell components.

Citing Articles

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References

Chaturvedi V, Qin J, Denning M, Choubey D, Diaz M, Nickoloff B . Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem. 1999; 274(33):23358-67. DOI: 10.1074/jbc.274.33.23358. View

Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson C . Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004; 6(12):1221-8. DOI: 10.1038/ncb1192. View

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A . Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003; 112(12):1809-20. PMC: 297002. DOI: 10.1172/JCI20039. View

Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann R . Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci. 2000; 113 ( Pt 7):1189-98. DOI: 10.1242/jcs.113.7.1189. View

Arico S, Petiot A, Bauvy C, Dubbelhuis P, Meijer A, Codogno P . The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2001; 276(38):35243-6. DOI: 10.1074/jbc.C100319200. View

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View

Linskens M, Feng J, Andrews W, Enlow B, Saati S, Tonkin L . Cataloging altered gene expression in young and senescent cells using enhanced differential display. Nucleic Acids Res. 1995; 23(16):3244-51. PMC: 307184. DOI: 10.1093/nar/23.16.3244. View

Pattingre S, Tassa A, Qu X, Garuti R, Liang X, Mizushima N . Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005; 122(6):927-39. DOI: 10.1016/j.cell.2005.07.002. View

Roberts P, Moshitch-Moshkovitz S, Kvam E, OToole E, Winey M, Goldfarb D . Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell. 2003; 14(1):129-41. PMC: 140233. DOI: 10.1091/mbc.e02-08-0483. View

10.

Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K . Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001; 152(4):657-68. PMC: 2195787. DOI: 10.1083/jcb.152.4.657. View

11.

Kagan V, Fabisiak J, Shvedova A, Tyurina Y, Tyurin V, Schor N . Oxidative signaling pathway for externalization of plasma membrane phosphatidylserine during apoptosis. FEBS Lett. 2000; 477(1-2):1-7. DOI: 10.1016/s0014-5793(00)01707-5. View

12.

Sansal I, Sellers W . The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004; 22(14):2954-63. DOI: 10.1200/JCO.2004.02.141. View

13.

Degterev A, Boyce M, Yuan J . A decade of caspases. Oncogene. 2003; 22(53):8543-67. DOI: 10.1038/sj.onc.1207107. View

14.

Allen D, Riviere J, Monteiro-Riviere N . Analysis of interleukin-8 release from normal human epidermal keratinocytes exposed to aliphatic hydrocarbons: delivery of hydrocarbons to cell cultures via complexation with alpha-cyclodextrin. Toxicol In Vitro. 2001; 15(6):663-9. DOI: 10.1016/s0887-2333(01)00075-3. View

15.

Kirkland R, Adibhatla R, Hatcher J, Franklin J . Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy. Neuroscience. 2002; 115(2):587-602. DOI: 10.1016/s0306-4522(02)00512-2. View

16.

Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S . Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004; 304(5676):1500-2. DOI: 10.1126/science.1096645. View

17.

Daido S, Yamamoto A, Fujiwara K, Sawaya R, Kondo S, Kondo Y . Inhibition of the DNA-dependent protein kinase catalytic subunit radiosensitizes malignant glioma cells by inducing autophagy. Cancer Res. 2005; 65(10):4368-75. DOI: 10.1158/0008-5472.CAN-04-4202. View

18.

Norsgaard H, Clark B, Rattan S . Distinction between differentiation and senescence and the absence of increased apoptosis in human keratinocytes undergoing cellular aging in vitro. Exp Gerontol. 1996; 31(5):563-70. DOI: 10.1016/0531-5565(96)00011-3. View

19.

Yoon I, Kim H, Kim Y, Song I, Kim W, Kim S . Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology. Exp Gerontol. 2004; 39(9):1369-78. DOI: 10.1016/j.exger.2004.07.002. View

20.

Hampel B, Malisan F, Niederegger H, Testi R, Jansen-Durr P . Differential regulation of apoptotic cell death in senescent human cells. Exp Gerontol. 2004; 39(11-12):1713-21. DOI: 10.1016/j.exger.2004.05.010. View