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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“This result was unexpected, since p16INK4A is commonly induced in scenarios that lead to premature senescence — for example, ectopic expression of an activated ras gene (27) or suboptimal cell-culture conditions (10).”
Background
The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence
Haferkamp, S., Tran, S. L., Becker, T. M., Scurr, L. L., Kefford, R. F., & Rizos, H. (2009) · Aging · doi:10.18632/aging.100051 · Cited by 77
Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling
Geserick, C., Tejera, Á. M., González‐Suárez, E., Klatt, P., & Blasco, M. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209465 · Cited by 71
“…of mTert in primary murine cells promotes growth, immortalization, and colony formation Telomerase overexpression is sufficient to immortalize many human cell types by maintaining telomeres above a critical threshold length (Bodnar et al., 1998; Dickson et al., 2000; Ramirez et al., 2001).”
Background
Bile salt exposure increases proliferation through p38 and ERK MAPK pathways in a non-neoplastic Barrett's cell line.
Jaiswal, K., Lopez-Guzman, C., Souza, R., Spechler, S., & Sarosi, G. (2006) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00167.2005 · Cited by 76
“To create feeder layer cells (1–3 10(6) cells/100-mm dish), Swiss 3T3 cells were treated with mitomycin C (10 g/ml for 2 h) as previously described(21).”
Method
Lentivector-Mediated Transfer of Bmi-1 and Telomerase in Muscle Satellite Cells Yields a Duchenne Myoblast Cell Line with Long-Term Genotypic and Phenotypic Stability
Cudré-Mauroux, C., Occhiodoro, T., König, S., Salmon, P., Bernheim, L., & Trono, D. (2003) · Human Gene Therapy · doi:10.1089/104303403322495034 · Cited by 86
“However, p16 accumulation was also suggested to be a result of inadequate growth conditions (Dickson et al., 2000; Herbert et al., 2002; Kiyono et al., 1998; Ramirez et al., 2001; Yaswen and Stampfer, 2002).”
p16INK4a inactivation is not required to immortalize human mammary epithelial cells
Herbert, B., Wright, W. E., & Shay, J. W. (2002) · Oncogene · doi:10.1038/sj.onc.1205902 · Cited by 86
“The premature growth arrest and loss of p16 in several epithelial cell types are due to inadequate growth conditions that can be overcome by the use of feeder layers (Ramirez et al., 2001; Shay and Wright, 2002).”
BackgroundMethodSelf-citation
Multiple stages of malignant transformation of human endothelial cells modelled by co-expression of telomerase reverse transcriptase, SV40 T antigen and oncogenic N-ras
MacKenzie, K. L., Franco, S., Naiyer, A. J., May, C., Sadelain, M., Rafii, S., & Moore, M. A. S. (2002) · Oncogene · doi:10.1038/sj.onc.1205425 · Cited by 71
“A recent investigation suggested that hTERT- Oncogene mediated immortalization is hampered by inadequate culture conditions (Ramirez et al., 2001).”
Background
Cancer-related inflammation and Barrett's carcinogenesis: interleukin-6 and STAT3 mediate apoptotic resistance in transformed Barrett's cells.
Zhang, H.-Y., Zhang, Q.-Y., Zhang, X., Yu, C.-H., Huo, X., Cheng, E., Wang, D. H., Spechler, S., & Souza, R. (2011) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00458.2010 · Cited by 74
“The nontransformed BAR-T, BAR-T p53RNAi, and BAR-T H-Ras-expressing (clone R6 and R7) cell lines were cocultured with a fibroblast feeder layer as previously described (12, 19).”
Method
Early loss of proliferative potential of human peritoneal mesothelial cells in culture: the role of p16INK4a-mediated premature senescence
Książek, K., Piwocka, K., Brzezińska, A., Sikora, E., Zabel, M., Bręborowicz, A., Jörres, A., & Witowski, J. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01086.2005 · Cited by 68
“On the other hand, it appears that some cell types may senesce rapidly in a telomere-independent manner in response to inadequate culture conditions (33).”
BackgroundInfluential
Transplantable cultivated mucosal epithelial sheet for ocular surface reconstruction.
Kinoshita, S., Koizumi, N., & Nakamura, T. (2004) · Experimental Eye Research · doi:10.1016/j.exer.2003.09.004 · Cited by 74
A keratinocyte hypermotility/growth-arrest response involving laminin 5 and p16INK4A activated in wound healing and senescence.
Natarajan, E., Omobono, J. D., Guo, Z.-Y., Hopkinson, S., Lazar, A., Brenn, T., Jones, J. C. R., & Rheinwald, J. (2006) · American Journal of Pathology · doi:10.2353/ajpath.2006.051027 · Cited by 73
Replicative senescence of hematopoietic stem cells during serial transplantation: does telomere shortening play a role?
Allsopp, R., & Weissman, I. L. (2002) · Oncogene · doi:10.1038/sj.onc.1205314 · Cited by 71
“…into HDF, retinal pigment epithelial cells, and endothelial cells in vitro, and in all cases, telomerase activity was restored, telomere length was maintained during culture, and replicative senescence was postponed inde®nitely (Bodnar et al., 1998; Yang et al., 1999; Ramirez et al., 2001).”
Background
Experimental models of human bladder carcinogenesis.
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Immortalized keratinocyte lines derived from human embryonic stem cells
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Abolition of Cyclin-Dependent Kinase Inhibitor p16 Ink4a and p21 Cip1/Waf1 Functions Permits Ras-Induced Anchorage-Independent Growth in Telomerase-Immortalized Human Fibroblasts
Wei, W., Jobling, W. A., Chen, W., Hahn, W. C., & Sedivy, J. M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.8.2859-2870.2003 · Cited by 68
“The extent to which mutations in these pathways are necessary for immortalization in addition to the expression of telomerase has been controversial (26, 47 , 50, 61).”
Background
In Vitro Model of the Epidermis
Arnette, C. R., Koetsier, J. L., Hoover, P., Getsios, S., & Green, K. J. (2015) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2015.07.015 · Cited by 67
Lessons from senescence: Chromatin maintenance in non-proliferating cells
Singh, T., & Adams, P. D. (2011) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.07.014 · Cited by 80
Proteostasis failure and cellular senescence in long‐term cultured postmitotic rat neurons
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Successful immortalization of mesenchymal progenitor cells derived from human placenta and the differentiation abilities of immortalized cells
Zhang, X., Soda, Y., Takahashi, K., Bai, Y., Mitsuru, A., Igura, K., Satoh, H., Yamaguchi, S., Tani, K., Tojo, A., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.125 · Cited by 63
Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1
Benanti, J. A., Williams, D. K., Robinson, K. L., Ozer, H. L., & Galloway, D. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7385-7397.2002 · Cited by 58
“Fibroblasts can be induced to arrest after fewer divisions, with elevated p16 levels, if they are grown in chemically defined medium with low serum levels (35).”
Background
Dynamics of histone H3.3 deposition in proliferating and senescent cells reveals a DAXX-dependent targeting to PML-NBs important for pericentromeric heterochromatin organization
Corpet, A., Olbrich, T., Gwerder, M., Fink, D., & Stucki, M. (2013) · Cell Cycle · doi:10.4161/cc.26988 · Cited by 80
Characterisation of telomerase immortalised normal human oesophageal squamous cells
Morales, C. P., Gandia, K. G., Ramirez, R. D., Wright, W. E., Shay, J. W., & Spechler, S. J. (2003) · Gut · doi:10.1136/gut.52.3.327 · Cited by 53
Self-citation
p16 and ARF: activation of teenage proteins in old age
Ande, S., & Rudolph, K. L. (2004) · Journal of Clinical Investigation · doi:10.1172/jci23437 · Cited by 64
Regulation of Senescence in Cancer and Aging
Kong, Y., Cui, H., Ramkumar, C., & Zhang, H. (2011) · Journal of Aging Research · doi:10.4061/2011/963172 · Cited by 61
“ture [43–45], oxidative stress [46–48], DNA damage [49, 50], and inadequate culture conditions [48, 51, 52].”
Background
Identification of a Candidate Tumor-Suppressor Gene Specifically Activated during Ras-Induced Senescence
Barradas, M., Gonos, E. S., Zebedee, Z., Kolettas, E., Petropoulou, C., Delgado, M. D., León, J., Hara, E., & Serrano, M. (2002) · Experimental Cell Research · doi:10.1006/excr.2001.5434 · Cited by 67
Acid Has Antiproliferative Effects in Nonneoplastic Barrett's Epithelial Cells
Feagins, L., Zhang, H.-Y., Hormi-Carver, K. K., Quinones, M. H., Thomas, D., Zhang, X., Terada, L., Spechler, S., Ramirez, R., & Souza, R. (2007) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2006.01005.x · Cited by 61
“Cells were maintained in monolayer culture at 37◦C in humidified air with 5% CO2 and cocultured with a fibroblast feeder layer, ATCC Albino Swiss 3T3 fibroblast cells treated with mitomycin C (10 μg/mL for 2 h), as previously described (9).”
MethodSelf-citation
Evidence That High Telomerase Activity May Induce a Senescent-like Growth Arrest in Human Fibroblasts
Gorbunova, V. A., Seluanov, A., & Pereira‐Smith, O. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212944200 · Cited by 56
p16INK4a modulates p53 in primary human mammary epithelial cells.
Zhang, J., Pickering, C. R., Holst, C. R., Gauthier, M. L., & Tlsty, T. D. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1594 · Cited by 60
“There are arguments that HMEC are cultured under ‘‘stressed’’ conditions (31, 32 ), and if the interaction we have observed occurs during stress-induced conditions, it is very relevant to p53 function and the carcinogenic process.”
Background
Nek4 Regulates Entry into Replicative Senescence and the Response to DNA Damage in Human Fibroblasts
Nguyen, C. L., Possemato, R., Bauerlein, E. L., Xie, A., Scully, R., & Hahn, W. C. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00436-12 · Cited by 61
“In addition, overexpression of the telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) in presenescent human cells leads to telomere length stability and facilitates immortalization (4, 17, 19, 33, 48).”
Background
Efficient Genetic Method for Establishing Drosophila Cell Lines Unlocks the Potential to Create Lines of Specific Genotypes
Simcox, A. A., Mitra, S., Truesdell, S. L., Paul, L., Chen, T., Butchar, J. P., & Justiniano, S. E. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000142 · Cited by 68
“Both M1 and M2 can be bypassed if cells are supplied with telomerase to maintain telomere length [30].”
Background
Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines.
Feagins, L., Zhang, H.-Y., Zhang, X., Hormi-Carver, K. K., Thomas, T., Terada, L., Spechler, S., & Souza, R. (2008) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00373.2007 · Cited by 60
“The telomerase-immortalized NES and Barrett’s cell lines were cocultured with a fibroblast feeder layer as previously described (29).”
Method
Resveratrol delays replicative senescence of human mesothelial cells via mobilization of antioxidative and DNA repair mechanisms
Mikuła‐Pietrasik, J., Kuczmarska, A., Rubiś, B., Filas, V., Murias, M., Zieliński, P., Piwocka, K., & Książek, K. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.03.014 · Cited by 62
Premature senescence of mesothelial cells is associated with non-telomeric DNA damage
Książek, K., Passos, J. F., Olijslagers, S., Saretzki, G. C., Martin-Ruiz, C. M., & von Zglinicki, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.08.047 · Cited by 55
“HPMCs were found to enter senescence upon reaching up to only 10 PD with a concomitant up-regulation of p16 protein [10]—a robust marker of premature cell ageing [5].”
Background
Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance
Thompson, C. A. H., & Wong, J. M. Y. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200131125110 · Cited by 67
Cyclin-dependent kinase inhibitor p16INK4a and telomerase may co-modulate endothelial progenitor cells senescence
Yang, D., Liu, L., & Zheng, X. (2008) · Ageing Research Reviews · doi:10.1016/j.arr.2008.02.001 · Cited by 55
Human telomerase can immortalize Indian muntjac cells.
Zou, Y. S., Yi, X., Wright, W., & Shay, J. (2002) · Experimental Cell Research · doi:10.1006/excr.2002.5645 · Cited by 55
“Telomerase activity is absent in most primary normal human cells; however, ectopic expression of the catalytic subunit of telomerase in human fibroblast and epithelial cells can maintain the telomeres and extend the life span of these cells [4, 5 ].”
BackgroundSelf-citation
Oncogenic transformation and experimental models of human cancer
Anna, C. S. (2007) · Frontiers in bioscience · doi:10.2741/2661 · Cited by 56
“For example, human mammary epithelial cells (HMECs) and keratinocytes (44, 83, 88), when propagated in the presence of either a feeder layer or after suppression of p16 are immortalized by expression of hTERT (44, 45, 83, 88).”
Background
Runx2 Disruption Promotes Immortalization and Confers Resistance to Oncogene-Induced Senescence in Primary Murine Fibroblasts
Kilbey, A., Blyth, K., Wotton, S., Terry, A., Jenkins, A., Bell, M., Hanlon, L., Cameron, E. R., & Neil, J. C. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-3016 · Cited by 52
“advantage was refractory to the nonphysiologic conditions of in vitro culture (23, 24) but was amplified by low-dose UVC irradiation, suggesting that loss of Runx2 alters sensitivity to a”
A prospect of cell immortalization combined with matrix microenvironmental optimization strategy for tissue engineering and regeneration
Wang, Y., Chen, S., Yan, Z., & Pei, M. (2019) · Cell & Bioscience · doi:10.1186/s13578-018-0264-9 · Cited by 69
Telomere shortening in hematopoietic stem cell transplantation: A potential mechanism for late graft failure?
Awaya, N., Baerlocher, G. M., Manley, T. J., Sanders, J. E., Mielcarek, M. B., Torok‐Storb, B., & Lansdorp, P. M. (2002) · Transplantation and Cellular Therapy · doi:10.1053/bbmt.2002.v8.abbmt080597 · Cited by 51
Genetic and Epigenetic Changes in Mammary Epithelial Cells Identify a Subpopulation of Cells Involved in Early Carcinogenesis
BERMAN, H., ZHANG, J., CRAWFORD, Y. G., GAUTHIER, M. L., FORDYCE, C. A., McDERMOTT, K. M., SIGAROUDINIA, M., KOZAKIEWICZ, K., & TLSTY, T. D. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.051 · Cited by 51
“2) (Brenner et al. 1998; Foster et al. 1998; Huschtscha et al. 1998; Ramirez et al. 2001) due to the hypermethylation of the p16INK4a promoter sequences.”
Background
Conditional reprogramming: next generation cell culture
Wu, X., Wang, S., Li, M., Li, J., Shen, J., Zhao, Y., Pang, J., Wen, Q., Chen, M., Wei, B., et al. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.011 · Cited by 61
Immortalization of bovine capillary endothelial cells by hTERT alone involves inactivation of endogenous p16 INK4A /pRb
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Unlike Esophageal Squamous Cells, Barrett's Epithelial Cells Resist Apoptosis by Activating the Nuclear Factor-κB Pathway
Hormi-Carver, K. K., Zhang, X., Zhang, H. Y., Whitehead, R. H., Terada, L. S., Spechler, S. J., & Souza, R. F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3703 · Cited by 43
“with a fibroblast feeder layer as previously described (20).”
Background
Inactivation of p16 INK4a (inhibitor of cyclin‐dependent kinase 4A) immortalizes primary human keratinocytes by maintaining cells in the stem cell compartment
Maurelli, R., Zambruno, G., Guerra, L., Abbruzzese, C., Dimri, G. P., Gellini, M., Bondanza, S., & Dellambra, E. (2006) · The FASEB Journal · doi:10.1096/fj.05-4480fje · Cited by 54
“Moreover, it has been reported that replicative senescence in human epidermal keratinocytes is solely dependent on telomere length, suggesting that the p16/Rb pathway constitutes a stress-induced senescence mechanism consequent to inadequate culture conditions (21, 22).”
Background
Senescence-like changes induced by expression of p21Waf1/Cip1 in NIH3T3 cell line
Chen, X., Zhang, W., Gao, Y., Su, X., & Zhai, Z. H. (2002) · Cell Research · doi:10.1038/sj.cr.7290129 · Cited by 47
“Thus, counting cell divisions rather than arresting growth is the distinguishing characteristic of replicative senescence[16], [17].”
Background

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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