Cited by 444Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

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

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Ramirez, Ruben D., Morales, Carmela P., Herbert, Brittney-Shea, Rohde, Jeffrey M., Passons, Christina, Shay, Jerry W., Wright, Woodring E.·2001·Genes & Development

DOI 10.1101/gad.859201PMC PMC312628

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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.

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Downregulation of Wnt Signaling Is a Trigger for Formation of Facultative Heterochromatin and Onset of Cell Senescence in Primary Human Cells
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“Senescence is also caused by cellular stresses, inadequate growth conditions, and shortened telomeres that result from repeated rounds of cell division (Campisi, 2005; Ramirez et al., 2001).”
Background
Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence
Jacobs, J. J. L., & de Lange, T. (2004) · Current Biology · doi:10.1016/j.cub.2004.12.025 · Cited by 237
Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci
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Cell cycle status in human corneal endothelium
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“This physiological response appears to trigger growth inhibition via activation of tumor suppressor genes, such as p16, p19, p53, and p21 (Alcorta et al. 1996; Kiyono et al. 1998; Stein et al. 1999; Ramirez et al. 2001; Randle et al. 2001; Rheinwald et al. 2002; Schmitt et al. 2002; Tyner et al. 2002).”
Background
Telomerase is not an oncogene
Harley, C. B. (2002) · Oncogene · doi:10.1038/sj.onc.1205076 · Cited by 194
Telomere biology in Metazoa
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Self-citation
Immortalized Epithelial Cells Derived From Human Colon Biopsies Express Stem Cell Markers and Differentiate In Vitro
Roig, A. I., Eskiocak, U., Hight, S. K., Kim, S. B., Delgado, O., Souza, R. F., Spechler, S. J., Wright, W. E., & Shay, J. W. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.11.052 · Cited by 180
Self-citation
Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging
Adams, P. D. (2007) · Gene · doi:10.1016/j.gene.2007.04.020 · Cited by 182
“As well as activated oncogenes, senescence is caused by shortened telomeres that result from repeated rounds of cell division, and inadequate in vitro growth conditions and other cellular stresses (20,59,101,136).”
Background
Stable Cellular Senescence Is Associated with Persistent DDR Activation
Fumagalli, M., Rossiello, F., Mondello, C., & d’Adda di Fagagna, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110969 · Cited by 183
“S2 and [45]) that has been observed associated with growth arrest in cells grown under inadequate conditions, such as exposure to oxidative stress or strong mitogenic stimuli [50–52].”
Background
Human lung epithelial cell cultures for analysis of inhaled toxicants: Lessons learned and future directions
Hiemstra, P. S., Grootaers, G., van der Does, A. M., Krul, C. A. M., & Kooter, I. M. (2017) · Toxicology in Vitro · doi:10.1016/j.tiv.2017.11.005 · Cited by 210
“It has been demonstrated that premature growth arrest of other epithelial cells (keratinocytes and mammary epithelial cells) is associated with increases in the cyclindependent kinase (Cdk) inhibitor p16INK4a (Ramirez et al., 2001).”
Background
Definition of pRB- and p53-Dependent and -Independent Steps in HIRA/ASF1a-Mediated Formation of Senescence-Associated Heterochromatin Foci
Ye, X., Zerlanko, B. J., Zhang, R., Somaiah, N., Lipinski, M., Salomoni, P., & Adams, P. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01592-06 · Cited by 177
“As well as activated oncogenes, senescence is caused by shortened telomeres that result from repeated rounds of cell division, cellular stresses, and inadequate growth conditions (11, 32, 52, 66).”
Background
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53
Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200904105 · Cited by 172
“However, because human p16Ink4a gene expression is also induced by tissue culture–imposed stress (Ramirez et al., 2001; Benanti and Galloway, 2004; Ince et al., 2007; Shay and Wright, 2007), it remains unclear whether the induction of human p16Ink4a gene expression in tissuecultured cells truly…”
Regulation of growth arrest in senescence: Telomere damage is not the end of the story
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BackgroundSelf-citation
Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival
Kang, M., Kim, R. H., Kim, S. J., Yip, F. K., Shin, K.-H., Dimri, G. P., Christensen, R. E., Han, T., & Park, N.-H. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603529 · Cited by 164
“The extrinsic senescence is telomere-independent and triggered in cells after exposure to environmental factors, such as genotoxic stress, in vitro culture shock, and oncogenic stimuli (Serrano et al, 1997; Ramirez et al, 2001; Itahana et al, 2004; Chen et al, 2005; Dimri, 2005).”
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Cell senescence and cancer
Mathon, N. F., & Lloyd, A. C. (2001) · Nature reviews. Cancer · doi:10.1038/35106045 · Cited by 313
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Background
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Granger, M. P., Wright, W. E., & Shay, J. W. (2002) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(01)00188-3 · Cited by 159
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BackgroundSelf-citation
Molecular Distinctions between Stasis and Telomere Attrition Senescence Barriers Shown by Long-term Culture of Normal Human Mammary Epithelial Cells
Garbe, J. C., Bhattacharya, S., Merchant, B., Bassett, E., Swisshelm, K. L., Feiler, H. S., Wyrobek, A. J., & Stampfer, M. R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0270 · Cited by 160
Cellular senescence and chromatin structure
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“On the other hand, various forms of stress including DNA-damaging agents, oncogenic activation, and inadequate culture conditions acutely induce a state that is indistinguishable from replicative senescence (Ogryzko et al. 1996; Serrano et al. 1997; Ramirez et al. 2001).”
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Background
Comparison of human mammary epithelial cells immortalized by simian virus 40 T-Antigen or by the telomerase catalytic subunit
Toouli, C. D., Huschtscha, L. I., Neumann, A. A., Noble, J. R., Colgin, L. M., Hukku, B., & Reddel, R. R. (2002) · Oncogene · doi:10.1038/sj.onc.1205014 · Cited by 144
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BackgroundInfluential
Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells
Huo, X., Juergens, S., Zhang, X., Rezaei, D., Yu, C., Strauch, E. D., Wang, J., Cheng, E., Meyer, F. P., Wang, D. H., et al. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00092.2011 · Cited by 140
“IEC-6 cells were cultured in DMEM with 10% FBS, and BAR-T cell lines were cocultured with a fibroblast feeder layer, as previously described (15, 26).”
Method
The Identification of Senescence-Specific Genes during the Induction of Senescence in Prostate Cancer Cells
Schwarze, S. R., Fu, V. X., Desotelle, J. A., Kenowski, M. L., & Jarrard, D. F. (2005) · Neoplasia · doi:10.1593/neo.05250 · Cited by 139
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Method
Increased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 140
Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer
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Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock
Munro, J., Barr, N. I., Ireland, H., Morrison, V., & Parkinson, E. K. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.01.017 · Cited by 141
Immortalisation and transformation revisited
Drayton, S. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00271-4 · Cited by 129
Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformationPreprint
Woo, R. A., & Poon, R. Y. C. (2004) · Genes & Development · doi:10.1101/gad.1165204 · Cited by 129
A Comprehensive Review on Mesenchymal Stem Cell Growth and Senescence
Książek, K. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0830 · Cited by 137
“1 The seminal studies on the senescence of cultured fibroblasts by Hayflick and Moorhead 2,3 were reproduced extensively and broadened by a large number of investigators on other types of somatic cells, including lymphocytes 4 endothelial, 5 epithelial, 6 and mesothelial cells.”
Immortalization of Primary Human Prostate Epithelial Cells by c-Myc
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CDK4 and cyclin D1 allow human myogenic cells to recapture growth property without compromising differentiation potential
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Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells
Gowrishankar, B., Somaiah, N., Zhang, R., Tang, Y., Hoffmann, J., Andrake, M., Ceulemans, H., Schultz, D., Marmorstein, R., & Adams, P. D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01047-08 · Cited by 156
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Background
Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging
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“However, these parameters lack the precise molecular basis and specificity (Robles and Adami, 1998; Severino et al., 2000; Ramirez et al., 2001; Romanov et al., 2001).”
BackgroundInfluential
Co-Expression of p16INK4A and Laminin 5 γ2 by Microinvasive and Superficial Squamous Cell Carcinomas in Vivo and by Migrating Wound and Senescent Keratinocytes in Culture
Natarajan, E., Saeb, M., Crum, C. P., Woo, S. B., McKee, P. H., & Rheinwald, J. G. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63677-2 · Cited by 114
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NON‐CORONARY HEART DISEASE IN DIALYSIS PATIENTS: Hypertrophy and Fibrosis in the Cardiomyopathy of Uremia—Beyond Coronary Heart Disease
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Genetic and Epigenetic Changes in Mammary Epithelial Cells May Mimic Early Events in Carcinogenesis
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A three-dimensional model of differentiation of immortalized human bronchial epithelial cells
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Self-citation
Are there roles for brain cell senescence in aging and neurodegenerative disorders?
Tan, F. C. C., Hutchison, E. R., Eitan, E., & Mattson, M. P. (2014) · Biogerontology · doi:10.1007/s10522-014-9532-1 · Cited by 116
“…seen in response to long-term exposure to sub- cytotoxic doses of a number of stressors including oxidative stress (Chen et al. 1995), UVB radiation (Medrano et al. 1995), artificial and inadequate culture conditions ((Ramirez et al. 2001; Sherr and DePinho 2000) for a review; also see Fig.”

Authors: Ramirez, R. D., Morales, C. P., Herbert, B.-S., Rohde, J. M., Passons, C., Shay, J. W., & Wright, W. E.
Affiliations: The University of Texas Southwestern Medical Center (US)
ORCID: Herbert, Brittney-Shea
Shay, Jerry W.
Wright, Woodring E.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2001-02-15
Volume: 15
Issue: 4
Pages: 398-403
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.859201
PMC: PMC312628
OpenAlex: W2136840198
Cited by: 444
References: 0
Citations by year: 2026: 4 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 12 · 2015: 9 · 2014: 14 · 2013: 8 · 2012: 12
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Ellison Medical Foundation
National Institute on Aging (AG 01228, R01AG001228)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: replicative senescence, telomere shortening, telomerase, p16INK4a, retinoblastoma protein, cell immortalization, feeder layer, epithelial-mesenchymal interactions, keratinocytes, breast epithelial cells, fibroblasts, culture conditions
MeSH terms: Animals, Cell Division, Cell Line, Transformed, Culture Media, Epithelial Cells, Female, Fibroblasts, Humans, Mammary Glands, Animal, Skin, Keratinocytes, 3T3 Cells, Telomere, Cellular Senescence, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Mice

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

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