Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Sep;16(9):5210–5218. doi: 10.1128/mcb.16.9.5210

Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent.

V V Ogryzko 1, T H Hirai 1, V R Russanova 1, D A Barbie 1, B H Howard 1
PMCID: PMC231521  PMID: 8756678

Abstract

Human diploid fibroblasts (HDF) complete a limited number of cell divisions before entering a growth arrest state that is termed replicative senescence. Two histone deacetylase inhibitors, sodium butyrate and trichostatin A, dramatically reduce the HDF proliferative life span in a manner that is dependent on one or more cell doublings in the presence of these agents. Cells arrested and subsequently released from histone deacetylase inhibitors display markers of senescence and exhibit a persistent G1 block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen. Average telomere length in prematurely arrested cells is greater than in senescent cells, reflecting a lower number of population doublings completed by the former. Taken together, these results support the view that one component of HDF senescence mimics a cell cycle-dependent drift in differentiation state and that propagation of HDF in histone deacetylase inhibitors accentuates this component.

Full Text

The Full Text of this article is available as a PDF (572.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allsopp R. C., Vaziri H., Patterson C., Goldstein S., Younglai E. V., Futcher A. B., Greider C. W., Harley C. B. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10114–10118. doi: 10.1073/pnas.89.21.10114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Annunziato A. T., Seale R. L. Histone deacetylation is required for the maturation of newly replicated chromatin. J Biol Chem. 1983 Oct 25;258(20):12675–12684. [PubMed] [Google Scholar]
  3. Atadja P. W., Stringer K. F., Riabowol K. T. Loss of serum response element-binding activity and hyperphosphorylation of serum response factor during cellular aging. Mol Cell Biol. 1994 Jul;14(7):4991–4999. doi: 10.1128/mcb.14.7.4991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bayreuther K., Rodemann H. P., Hommel R., Dittmann K., Albiez M., Francz P. I. Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5112–5116. doi: 10.1073/pnas.85.14.5112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bischoff F. Z., Yim S. O., Pathak S., Grant G., Siciliano M. J., Giovanella B. C., Strong L. C., Tainsky M. A. Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization. Cancer Res. 1990 Dec 15;50(24):7979–7984. [PubMed] [Google Scholar]
  6. Boffa L. C., Mariani M. R., Parker M. I. Selective hypermethylation of transcribed nucleosomal DNA by sodium butyrate. Exp Cell Res. 1994 Apr;211(2):420–423. doi: 10.1006/excr.1994.1107. [DOI] [PubMed] [Google Scholar]
  7. Boyd A. W., Metcalf D. Induction of differentiation in HL60 leukaemic cells: a cell cycle dependent all-or-none event. Leuk Res. 1984;8(1):27–43. doi: 10.1016/0145-2126(84)90029-8. [DOI] [PubMed] [Google Scholar]
  8. Brownell J. E., Zhou J., Ranalli T., Kobayashi R., Edmondson D. G., Roth S. Y., Allis C. D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell. 1996 Mar 22;84(6):843–851. doi: 10.1016/s0092-8674(00)81063-6. [DOI] [PubMed] [Google Scholar]
  9. Candido E. P., Reeves R., Davie J. R. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978 May;14(1):105–113. doi: 10.1016/0092-8674(78)90305-7. [DOI] [PubMed] [Google Scholar]
  10. Catania J., Fairweather D. S. DNA methylation and cellular ageing. Mutat Res. 1991 Mar-Nov;256(2-6):283–293. doi: 10.1016/0921-8734(91)90019-8. [DOI] [PubMed] [Google Scholar]
  11. Cattanach B. M. Position effect variegation in the mouse. Genet Res. 1974 Jun;23(3):291–306. doi: 10.1017/s0016672300014932. [DOI] [PubMed] [Google Scholar]
  12. Chen Q., Ames B. N. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4130–4134. doi: 10.1073/pnas.91.10.4130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chen Q., Fischer A., Reagan J. D., Yan L. J., Ames B. N. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4337–4341. doi: 10.1073/pnas.92.10.4337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cook K. R., Karpen G. H. A rosy future for heterochromatin. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5219–5221. doi: 10.1073/pnas.91.12.5219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cosgrove D. E., Cox G. S. Effects of sodium butyrate and 5-azacytidine on DNA methylation in human tumor cell lines: variable response to drug treatment and withdrawal. Biochim Biophys Acta. 1990 Sep 10;1087(1):80–86. doi: 10.1016/0167-4781(90)90124-k. [DOI] [PubMed] [Google Scholar]
  16. Cristofalo V. J., Pignolo R. J. Replicative senescence of human fibroblast-like cells in culture. Physiol Rev. 1993 Jul;73(3):617–638. doi: 10.1152/physrev.1993.73.3.617. [DOI] [PubMed] [Google Scholar]
  17. Csordas A. On the biological role of histone acetylation. Biochem J. 1990 Jan 1;265(1):23–38. doi: 10.1042/bj2650023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dell'Orco R. T., Mertens J. G., Kruse P. F., Jr Doubling potential, calendar time, and senescence of human diploid cells in culture. Exp Cell Res. 1973 Mar 15;77(1):356–360. doi: 10.1016/0014-4827(73)90588-0. [DOI] [PubMed] [Google Scholar]
  19. Dimri G. P., Lee X., Basile G., Acosta M., Scott G., Roskelley C., Medrano E. E., Linskens M., Rubelj I., Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363–9367. doi: 10.1073/pnas.92.20.9363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dulić V., Drullinger L. F., Lees E., Reed S. I., Stein G. H. Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11034–11038. doi: 10.1073/pnas.90.23.11034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Dunaief J. L., Strober B. E., Guha S., Khavari P. A., Alin K., Luban J., Begemann M., Crabtree G. R., Goff S. P. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell. 1994 Oct 7;79(1):119–130. doi: 10.1016/0092-8674(94)90405-7. [DOI] [PubMed] [Google Scholar]
  22. Fairweather D. S., Fox M., Margison G. P. The in vitro lifespan of MRC-5 cells is shortened by 5-azacytidine-induced demethylation. Exp Cell Res. 1987 Jan;168(1):153–159. doi: 10.1016/0014-4827(87)90424-1. [DOI] [PubMed] [Google Scholar]
  23. Foss F. M., Veillette A., Sartor O., Rosen N., Bolen J. B. Alterations in the expression of pp60c-src and p56lck associated with butyrate-induced differentiation of human colon carcinoma cells. Oncogene Res. 1989;5(1):13–23. [PubMed] [Google Scholar]
  24. Giordano T., Howard T. H., Coleman J., Sakamoto K., Howard B. H. Isolation of a population of transiently transfected quiescent and senescent cells by magnetic affinity cell sorting. Exp Cell Res. 1991 Jan;192(1):193–197. doi: 10.1016/0014-4827(91)90175-t. [DOI] [PubMed] [Google Scholar]
  25. Goldstein S. Replicative senescence: the human fibroblast comes of age. Science. 1990 Sep 7;249(4973):1129–1133. doi: 10.1126/science.2204114. [DOI] [PubMed] [Google Scholar]
  26. Goldstein S., Singal D. P. Senescence of cultured human fibroblasts: mitotic versus metabolic time. Exp Cell Res. 1974 Oct;88(2):359–364. doi: 10.1016/0014-4827(74)90252-3. [DOI] [PubMed] [Google Scholar]
  27. Gorman C. M., Howard B. H., Reeves R. Expression of recombinant plasmids in mammalian cells is enhanced by sodium butyrate. Nucleic Acids Res. 1983 Nov 11;11(21):7631–7648. doi: 10.1093/nar/11.21.7631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Gorman S. D., Cristofalo V. J. Reinitiation of cellular DNA synthesis in BrdU-selected nondividing senescent WI-38 cells by simian virus 40 infection. J Cell Physiol. 1985 Oct;125(1):122–126. doi: 10.1002/jcp.1041250116. [DOI] [PubMed] [Google Scholar]
  29. Grove G. L., Mitchell R. B. DNA microdensitometry as a measure of cycling-non-cycling activity in aged human diploid cells in culture. Mech Ageing Dev. 1974 Sep-Oct;3(3-4):235–240. doi: 10.1016/0047-6374(74)90019-0. [DOI] [PubMed] [Google Scholar]
  30. Hara E., Tsurui H., Shinozaki A., Nakada S., Oda K. Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem Biophys Res Commun. 1991 Aug 30;179(1):528–534. doi: 10.1016/0006-291x(91)91403-y. [DOI] [PubMed] [Google Scholar]
  31. Hara E., Yamaguchi T., Nojima H., Ide T., Campisi J., Okayama H., Oda K. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem. 1994 Jan 21;269(3):2139–2145. [PubMed] [Google Scholar]
  32. Harley C. B., Futcher A. B., Greider C. W. Telomeres shorten during ageing of human fibroblasts. Nature. 1990 May 31;345(6274):458–460. doi: 10.1038/345458a0. [DOI] [PubMed] [Google Scholar]
  33. Hastie N. D., Dempster M., Dunlop M. G., Thompson A. M., Green D. K., Allshire R. C. Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990 Aug 30;346(6287):866–868. doi: 10.1038/346866a0. [DOI] [PubMed] [Google Scholar]
  34. Hearn M. G., Hedrick A., Grigliatti T. A., Wakimoto B. T. The effect of modifiers of position-effect variegation on the variegation of heterochromatic genes of Drosophila melanogaster. Genetics. 1991 Aug;128(4):785–797. doi: 10.1093/genetics/128.4.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Henikoff S. A reconsideration of the mechanism of position effect. Genetics. 1994 Sep;138(1):1–5. doi: 10.1093/genetics/138.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ho S. B., Yan P. S., Dahiya R., Neuschwander-Tetri B. A., Basbaum C., Kim Y. S. Stable differentiation of a human colon adenocarcinoma cell line by sodium butyrate is associated with multidrug resistance. J Cell Physiol. 1994 Aug;160(2):213–226. doi: 10.1002/jcp.1041600202. [DOI] [PubMed] [Google Scholar]
  37. Ide T., Tsuji Y., Ishibashi S., Mitsui Y. Reinitiation of host DNA synthesis in senescent human diploid cells by infection with Simian virus 40. Exp Cell Res. 1983 Feb;143(2):343–349. doi: 10.1016/0014-4827(83)90060-5. [DOI] [PubMed] [Google Scholar]
  38. Jeppesen P., Turner B. M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell. 1993 Jul 30;74(2):281–289. doi: 10.1016/0092-8674(93)90419-q. [DOI] [PubMed] [Google Scholar]
  39. Kennedy B. K., Austriaco N. R., Jr, Zhang J., Guarente L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell. 1995 Feb 10;80(3):485–496. doi: 10.1016/0092-8674(95)90499-9. [DOI] [PubMed] [Google Scholar]
  40. Koonin E. V., Zhou S., Lucchesi J. C. The chromo superfamily: new members, duplication of the chromo domain and possible role in delivering transcription regulators to chromatin. Nucleic Acids Res. 1995 Nov 11;23(21):4229–4233. doi: 10.1093/nar/23.21.4229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kruh J. Effects of sodium butyrate, a new pharmacological agent, on cells in culture. Mol Cell Biochem. 1982 Feb 5;42(2):65–82. doi: 10.1007/BF00222695. [DOI] [PubMed] [Google Scholar]
  42. Laurenson P., Rine J. Silencers, silencing, and heritable transcriptional states. Microbiol Rev. 1992 Dec;56(4):543–560. doi: 10.1128/mr.56.4.543-560.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Marks P. A., Richon V. M., Kiyokawa H., Rifkind R. A. Inducing differentiation of transformed cells with hybrid polar compounds: a cell cycle-dependent process. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10251–10254. doi: 10.1073/pnas.91.22.10251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Marks P. A., Rifkind R. A. Erythroleukemic differentiation. Annu Rev Biochem. 1978;47:419–448. doi: 10.1146/annurev.bi.47.070178.002223. [DOI] [PubMed] [Google Scholar]
  45. Martin C. C., McGowan R. Genotype-specific modifiers of transgene methylation and expression in the zebrafish, Danio rerio. Genet Res. 1995 Feb;65(1):21–28. doi: 10.1017/s0016672300032973. [DOI] [PubMed] [Google Scholar]
  46. Martin G. M., Sprague C. A., Norwood T. H., Pendergrass W. R. Clonal selection, attenuation and differentiation in an in vitro model of hyperplasia. Am J Pathol. 1974 Jan;74(1):137–154. [PMC free article] [PubMed] [Google Scholar]
  47. Migeon B. R., Axelman J., Beggs A. H. Effect of ageing on reactivation of the human X-linked HPRT locus. Nature. 1988 Sep 1;335(6185):93–96. doi: 10.1038/335093a0. [DOI] [PubMed] [Google Scholar]
  48. Morrow C. S., Nakagawa M., Goldsmith M. E., Madden M. J., Cowan K. H. Reversible transcriptional activation of mdr1 by sodium butyrate treatment of human colon cancer cells. J Biol Chem. 1994 Apr 8;269(14):10739–10746. [PubMed] [Google Scholar]
  49. Mottus R., Reeves R., Grigliatti T. A. Butyrate suppression of position-effect variegation in Drosophila melanogaster. Mol Gen Genet. 1980;178(2):465–469. doi: 10.1007/BF00270501. [DOI] [PubMed] [Google Scholar]
  50. Noda A., Ning Y., Venable S. F., Pereira-Smith O. M., Smith J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90–98. doi: 10.1006/excr.1994.1063. [DOI] [PubMed] [Google Scholar]
  51. Ogryzko V. V., Hirai T. H., Shih C. E., Howard B. H. Dissociation of retinoblastoma gene protein hyperphosphorylation and commitment to enter S phase. J Virol. 1994 Jun;68(6):3724–3732. doi: 10.1128/jvi.68.6.3724-3732.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Olovnikov A. M. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973 Sep 14;41(1):181–190. doi: 10.1016/0022-5193(73)90198-7. [DOI] [PubMed] [Google Scholar]
  53. Parker M. I., de Haan J. B., Gevers W. DNA hypermethylation in sodium butyrate-treated WI-38 fibroblasts. J Biol Chem. 1986 Feb 25;261(6):2786–2790. [PubMed] [Google Scholar]
  54. Peacocke M., Campisi J. Cellular senescence: a reflection of normal growth control, differentiation, or aging? J Cell Biochem. 1991 Feb;45(2):147–155. doi: 10.1002/jcb.240450205. [DOI] [PubMed] [Google Scholar]
  55. Pillus L., Rine J. Epigenetic inheritance of transcriptional states in S. cerevisiae. Cell. 1989 Nov 17;59(4):637–647. doi: 10.1016/0092-8674(89)90009-3. [DOI] [PubMed] [Google Scholar]
  56. Pirrotta V., Rastelli L. White gene expression, repressive chromatin domains and homeotic gene regulation in Drosophila. Bioessays. 1994 Aug;16(8):549–556. doi: 10.1002/bies.950160808. [DOI] [PubMed] [Google Scholar]
  57. Quinn L. S., Norwood T. H., Nameroff M. Myogenic stem cell commitment probability remains constant as a function of organismal and mitotic age. J Cell Physiol. 1988 Mar;134(3):324–336. doi: 10.1002/jcp.1041340303. [DOI] [PubMed] [Google Scholar]
  58. Reuter G., Spierer P. Position effect variegation and chromatin proteins. Bioessays. 1992 Sep;14(9):605–612. doi: 10.1002/bies.950140907. [DOI] [PubMed] [Google Scholar]
  59. Riabowol K., Schiff J., Gilman M. Z. Transcription factor AP-1 activity is required for initiation of DNA synthesis and is lost during cellular aging. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):157–161. doi: 10.1073/pnas.89.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Rivier D. H., Rine J. Silencing: the establishment and inheritance of stable, repressed transcription states. Curr Opin Genet Dev. 1992 Apr;2(2):286–292. doi: 10.1016/s0959-437x(05)80286-2. [DOI] [PubMed] [Google Scholar]
  61. Roberts T. W., Smith J. R. The proliferative potential of chick embryo fibroblasts: population doublings vs. time in culture. Cell Biol Int Rep. 1980 Dec;4(12):1057–1063. doi: 10.1016/0309-1651(80)90042-9. [DOI] [PubMed] [Google Scholar]
  62. Sakamoto K., Howard T., Ogryzko V., Xu N. Z., Corsico C. C., Jones D. H., Howard B. Relative mitogenic activities of wild-type and retinoblastoma binding-defective SV40 T antigens in serum-deprived and senescent human diploid fibroblasts. Oncogene. 1993 Jul;8(7):1887–1893. [PubMed] [Google Scholar]
  63. Schanz S., Steinbach P. Investigation of the "variable spreading" of X inactivation into a translocated autosome. Hum Genet. 1989 Jun;82(3):244–248. doi: 10.1007/BF00291163. [DOI] [PubMed] [Google Scholar]
  64. Sealy L., Chalkley R. The effect of sodium butyrate on histone modification. Cell. 1978 May;14(1):115–121. doi: 10.1016/0092-8674(78)90306-9. [DOI] [PubMed] [Google Scholar]
  65. Seshadri T., Campisi J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science. 1990 Jan 12;247(4939):205–209. doi: 10.1126/science.2104680. [DOI] [PubMed] [Google Scholar]
  66. Shaffer C. D., Wallrath L. L., Elgin S. C. Regulating genes by packaging domains: bits of heterochromatin in euchromatin? Trends Genet. 1993 Feb;9(2):35–37. doi: 10.1016/0168-9525(93)90171-D. [DOI] [PubMed] [Google Scholar]
  67. Shay J. W., Pereira-Smith O. M., Wright W. E. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res. 1991 Sep;196(1):33–39. doi: 10.1016/0014-4827(91)90453-2. [DOI] [PubMed] [Google Scholar]
  68. Simon J., Chiang A., Bender W., Shimell M. J., O'Connor M. Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products. Dev Biol. 1993 Jul;158(1):131–144. doi: 10.1006/dbio.1993.1174. [DOI] [PubMed] [Google Scholar]
  69. Sinclair D. A., Ruddell A. A., Brock J. K., Clegg N. J., Lloyd V. K., Grigliatti T. A. A cytogenetic and genetic characterization of a group of closely linked second chromosome mutations that suppress position-effect variegation in Drosophila melanogaster. Genetics. 1992 Feb;130(2):333–344. doi: 10.1093/genetics/130.2.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Smith J. R., Lincoln D. W., 2nd Aging of cells in culture. Int Rev Cytol. 1984;89:151–177. doi: 10.1016/s0074-7696(08)61303-0. [DOI] [PubMed] [Google Scholar]
  71. Sohal R. S., Allen R. G. Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis. Exp Gerontol. 1990;25(6):499–522. doi: 10.1016/0531-5565(90)90017-v. [DOI] [PubMed] [Google Scholar]
  72. Stadtman E. R. Protein oxidation and aging. Science. 1992 Aug 28;257(5074):1220–1224. doi: 10.1126/science.1355616. [DOI] [PubMed] [Google Scholar]
  73. Stein G. H., Beeson M., Gordon L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science. 1990 Aug 10;249(4969):666–669. doi: 10.1126/science.2166342. [DOI] [PubMed] [Google Scholar]
  74. Stein G. H., Drullinger L. F., Robetorye R. S., Pereira-Smith O. M., Smith J. R. Senescent cells fail to express cdc2, cycA, and cycB in response to mitogen stimulation. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11012–11016. doi: 10.1073/pnas.88.24.11012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Szekely L., Uzvolgyi E., Jiang W. Q., Durko M., Wiman K. G., Klein G., Sumegi J. Subcellular localization of the retinoblastoma protein. Cell Growth Differ. 1991 Jun;2(6):287–295. [PubMed] [Google Scholar]
  76. Thomas N. S., Burke L. C., Bybee A., Linch D. C. The phosphorylation state of the retinoblastoma (RB) protein in G0/G1 is dependent on growth status. Oncogene. 1991 Feb;6(2):317–322. [PubMed] [Google Scholar]
  77. Tsuji Y., Ide T., Ishibashi S. Correlation between the presence of T-antigen and the reinitiation of host DNA synthesis in senescent human diploid fibroblasts after SV40 infection. Exp Cell Res. 1983 Mar;144(1):165–169. doi: 10.1016/0014-4827(83)90450-0. [DOI] [PubMed] [Google Scholar]
  78. Tsukada M., Wada Y., Hamade N., Masuda H., Koizumi A. Stable Lyonization of X-linked pgk-1 gene during aging in normal tissues and tumors of mice carrying Searle's translocation. J Gerontol. 1991 Nov;46(6):B213–B216. doi: 10.1093/geronj/46.6.b213. [DOI] [PubMed] [Google Scholar]
  79. Vidali G., Boffa L. C., Bradbury E. M., Allfrey V. G. Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc Natl Acad Sci U S A. 1978 May;75(5):2239–2243. doi: 10.1073/pnas.75.5.2239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Wareham K. A., Lyon M. F., Glenister P. H., Williams E. D. Age related reactivation of an X-linked gene. 1987 Jun 25-Jul 1Nature. 327(6124):725–727. doi: 10.1038/327725a0. [DOI] [PubMed] [Google Scholar]
  81. Warner H. R., Campisi J., Cristofalo V. J., Miller R. A., Papaconstantinou J., Pereira-Smith O., Smith J. R., Wang E. Control of cell proliferation in senescent cells. J Gerontol. 1992 Nov;47(6):B185–B189. doi: 10.1093/geronj/47.6.b185. [DOI] [PubMed] [Google Scholar]
  82. Wilson V. L., Jones P. A. DNA methylation decreases in aging but not in immortal cells. Science. 1983 Jun 3;220(4601):1055–1057. doi: 10.1126/science.6844925. [DOI] [PubMed] [Google Scholar]
  83. Wright W. E., Shay J. W. Telomere positional effects and the regulation of cellular senescence. Trends Genet. 1992 Jun;8(6):193–197. doi: 10.1016/0168-9525(92)90232-s. [DOI] [PubMed] [Google Scholar]
  84. Yang L. Q., Hornsby P. J. Dissociation of senescence-associated changes in differentiated gene expression and replicative senescence in cultured adrenocortical cells. J Cell Sci. 1989 Dec;94(Pt 4):757–768. doi: 10.1242/jcs.94.4.757. [DOI] [PubMed] [Google Scholar]
  85. Yanishevsky R., Mendelsohn M. L., Mayall B. H., Cristofalo V. J. Proliferative capacity and DNA content of aging human diploid cells in culture: a cytophotometric and autoradiographic analysis. J Cell Physiol. 1974 Oct;84(2):165–170. doi: 10.1002/jcp.1040840202. [DOI] [PubMed] [Google Scholar]
  86. Yoshida M., Kijima M., Akita M., Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990 Oct 5;265(28):17174–17179. [PubMed] [Google Scholar]
  87. von Zglinicki T., Saretzki G., Döcke W., Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp Cell Res. 1995 Sep;220(1):186–193. doi: 10.1006/excr.1995.1305. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES