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PMID: 11230148 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions.

Genes & development ·Vol. 15 ·No. 4 ·2001-02-15 ·Pages 398-403

Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE

Abstract

Telomere shortening is the mechanism underlying replicative aging in fibroblasts. A variety of reports now claim that inactivation of the p16(INK4a)/pRB pathway is required in addition to telomere maintenance for the immortalization of cells such as skin keratinocytes and breast epithelial cells. We here show that the premature growth arrest of these cell types can be explained by an inadequate culture environment. Providing mesenchymal/epithelial interactions by cultivating the telomerase-expressing cells on feeder layers avoids the growth arrest associated with increased p16(INK4a). These results do not support a telomere-independent mechanism of replicative aging.

MeSH Terms
3T3 Cells Animals Cell Division Cell Line, Transformed Cellular Senescence/genetics Culture Media Cyclin-Dependent Kinase Inhibitor p16/biosynthesis Epithelial Cells/cytology Female Fibroblasts/cytology Humans Keratinocytes/cytology,enzymology Mammary Glands, Animal/cytology Mice Skin/cytology Telomerase/metabolism Telomere
Chemicals
Culture Media Cyclin-Dependent Kinase Inhibitor p16 Telomerase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ramirez R D
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
Morales C P
Herbert B S
Rohde J M
Passons C
Shay J W
Wright W E
References (38)
38 references, click to expand
  1. Telomere loss: mitotic clock or genetic time bomb?
    Mutat Res. 1991 Mar-Nov;256(2-6):271-82 PMID: 1722017
  2. The serial cultivation of human diploid cell strains.
    Exp Cell Res. 1961 Dec;25:585-621 PMID: 13905658
  3. 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):9363-7 PMID: 7568133
  4. Evidence for a new step in telomere maintenance.
    Cell. 1996 May 3;85(3):423-33 PMID: 8616897
  5. Telomerase activity in human germline and embryonic tissues and cells.
    Dev Genet. 1996;18(2):173-9 PMID: 8934879
  6. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
    Cell. 1997 Mar 7;88(5):593-602 PMID: 9054499
  7. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging.
    Oncogene. 1997 Jul 10;15(2):203-11 PMID: 9244355
  8. Cell aging in vivo and in vitro.
    Mech Ageing Dev. 1997 Oct;98(1):1-35 PMID: 9255755
  9. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.
    Cell. 1997 Oct 3;91(1):25-34 PMID: 9335332
  10. Extension of life-span by introduction of telomerase into normal human cells.
    Science. 1998 Jan 16;279(5349):349-52 PMID: 9454332
  11. Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics.
    Mol Cell Biol. 2000 Feb;20(4):1436-47 PMID: 10648628
  12. The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes.
    Hum Mol Genet. 2000 Feb 12;9(3):403-11 PMID: 10655550
  13. The p53 tumor suppressor protein does not regulate expression of its own inhibitor, MDM2, except under conditions of stress.
    Mol Cell Biol. 2000 Mar;20(6):2023-30 PMID: 10688649
  14. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3266-71 PMID: 10716710
  15. Genetic and epigenetic changes in human epithelial cells immortalized by telomerase.
    Am J Pathol. 2000 May;156(5):1537-47 PMID: 10793065
  16. Telomere shortening is proportional to the size of the G-rich telomeric 3'-overhang.
    J Biol Chem. 2000 Jun 30;275(26):19719-22 PMID: 10787419
  17. Evidence for a telomere-independent "clock" limiting RAS oncogene-driven proliferation of human thyroid epithelial cells.
    Mol Cell Biol. 2000 Aug;20(15):5690-9 PMID: 10891505
  18. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology.
    Nat Med. 2000 Aug;6(8):849-51 PMID: 10932210
  19. Cellular senescence: mitotic clock or culture shock?
    Cell. 2000 Aug 18;102(4):407-10 PMID: 10966103
  20. Properties of an epithelial cell type in culture: the epidermal keratinocyte and its dependence on products of the fibroblast.
    Prog Clin Biol Res. 1977;17:493-500 PMID: 928463
  21. Growth of normal human mammary cells in culture.
    In Vitro. 1980 May;16(5):415-25 PMID: 6993343
  22. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.
    Cell. 1985 Dec;43(2 Pt 1):405-13 PMID: 3907856
  23. Extended culture of mouse embryo cells without senescence: inhibition by serum.
    Science. 1987 Apr 10;236(4798):200-2 PMID: 3494308
  24. Telomeres shorten during ageing of human fibroblasts.
    Nature. 1990 May 31;345(6274):458-60 PMID: 2342578
  25. Serum amine oxidase activity contributes to crisis in mouse embryo cell lines.
    Proc Natl Acad Sci U S A. 1990 Jun;87(11):4340-4 PMID: 2349241
  26. TRF2 protects human telomeres from end-to-end fusions.
    Cell. 1998 Feb 6;92(3):401-13 PMID: 9476899
  27. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span.
    Curr Biol. 1998 Feb 26;8(5):279-82 PMID: 9501072
  28. Inactivation of p16 in human mammary epithelial cells by CpG island methylation.
    Mol Cell Biol. 1998 Apr;18(4):1793-801 PMID: 9528751
  29. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts.
    Oncogene. 1998 Mar 5;16(9):1113-23 PMID: 9528853
  30. Telomerase and cellular lifespan: ending the debate?
    Nat Biotechnol. 1998 May;16(5):396-7 PMID: 9592374
  31. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.
    Nature. 1998 Nov 5;396(6706):84-8 PMID: 9817205
  32. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype.
    Nat Genet. 1999 Jan;21(1):111-4 PMID: 9916802
  33. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase.
    Nat Genet. 1999 Jan;21(1):115-8 PMID: 9916803
  34. Positive correlation between mammalian life span and cellular resistance to stress.
    Free Radic Biol Med. 1999 Mar;26(5-6):495-500 PMID: 10218637
  35. p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells.
    Cancer Res. 1999 Jun 15;59(12):2957-64 PMID: 10383161
  36. Human endothelial cell life extension by telomerase expression.
    J Biol Chem. 1999 Sep 10;274(37):26141-8 PMID: 10473565
  37. Microarray analysis of replicative senescence.
    Curr Biol. 1999 Sep 9;9(17):939-45 PMID: 10508581
  38. The two-stage mechanism controlling cellular senescence and immortalization.
    Exp Gerontol. 1992 Jul-Aug;27(4):383-9 PMID: 1333985
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
Published
2001-02-15
Pages
398-403
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC312628
Subset
IM
Grants
NIA NIH HHS · R01 AG001228 · United States
NIA NIH HHS · AG01228 · United States
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