The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Likewise, telomere-dependent replicative senescence is thought to depend primarily on the p53 pathway (Ramirez et al., 2001; Herbig et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Ramirez et al., 2001
Experimental — accuracy not yet measuredIn the citing paper
“although cellular senescence in vitro may also occur without detectable DDR [31,32].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [31]
In the citing paper
“Telomerase activation and the resulting telomere-length maintenance leads to the bypass of senescence and ultimately to cell immortalization23,26,27.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 3×
“The same argument applies to the premature cellular senescence induced by Ras ( Serrano et al. 1997 ).”
BackgroundExtension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975
Self-citationTelomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., & Greider, C. W. (1997) · Cell · doi:10.1016/s0092-8674(01)80006-4 · Cited by 2,108
TRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · cited 3×
“2; Kiyono et al. 1998).”
BackgroundInfluentialVaziri, H., & Benchimol, S. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70109-5 · Cited by 1,003
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745
Zindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574
Robles, S. J., & Adami, G. R. (1998) · Oncogene · doi:10.1038/sj.onc.1201862 · Cited by 498
Research works printed but not linked: 29
- 10.1128/MCB.20.4.1436-1447.2000 · DOI · Paper page
- 10.1073/pnas.92.20.9363 · DOI · Paper page
- Foster, 1998, Inactivation of p16 in human mammary epithelial cells by CpG island methylation., Mol. Cell. Biol., 18, 1793, 10.1128/MCB.18.4.1793 · DOI
- Green, 1977, Properties of an epithelial cell type in culture: The epidermal keratinocyte and its dependence on products of the fibroblast., Prog. Clin. Biol. Res., 17, 493
- 10.1016/0092-8674(85)90170-9 · DOI · Paper page
- 10.1016/0921-8734(91)90018-7 · DOI · Paper page
- Hayflick, 1980, Cell Aging., Annual Review of Gerontology and Geriatrics, 1, 26
- Hayflick, 1961, The limited in vitro lifetime of human diploid cell strains., Exp. Cell Res., 25, 585, 10.1016/0014-4827(61)90192-6 · DOI · Paper page
- 10.1074/jbc.M002843200 · DOI
- Jarrard, 1999, p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells., Cancer Res., 59, 2957
- 10.1038/5056 · DOI
- 10.1128/MCB.20.15.5690-5699.2000 · DOI · Paper page
- 10.1073/pnas.050560997 · DOI · Paper page
- 10.1016/S0891-5849(98)00323-2 · DOI
- 10.1126/science.3494308 · DOI
- 10.1128/MCB.20.6.2023-2030.2000 · DOI
- 10.1038/5063 · DOI
- 10.1093/hmg/9.3.403 · DOI
- 10.1073/pnas.87.11.4340 · DOI
- Rheinwald J.G. (1989) Methods for clonal growth and serial cultivation of normal human epidermal keratinocytes and mesothelial cells. in Cell growth and division: A practical approach, ed Baserga R. (IRL, Oxford, UK), pp 81–94.
- Rubin, 1997, Cell aging in vivo and in vitro., Mech. Aging Dev., 98, 1, 10.1016/S0047-6374(97)00067-5 · DOI
- 10.1038/nbt0598-396 · DOI
- 10.1016/S0960-9822(99)80420-5 · DOI · Paper page
- Stampfer, 1980, Growth of normal human mammary cells in culture., In Vitro, 16, 415, 10.1007/BF02618365 · DOI
- 10.1016/S0092-8674(00)81120-4 · DOI
- 10.1016/0531-5565(92)90069-C · DOI · Paper page
- 10.1038/78592 · DOI · Paper page
- 10.1002/(SICI)1520-6408(1996)18:2<173::AID-DVG10>3.0.CO;2-3 · DOI · Paper page
- 10.1074/jbc.274.37.26141 · DOI
Cited by
Sorted by citations
Items 301–400 of 404
Cell culture and karyotype of Sakhalin sturgeon Acipenser mikadoi
Vishnyakova, K. S., Mugue, N., Zelenina, D., Mikodina, E. V., Kovaleva, O. A., Madan, G., & Yegorov, Y. (2009) · Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology · doi:10.1134/s1990747809010061 · Cited by 16
Gene Mutations and Aneuploidy: The Instability That Causes Cancer
Woo, R. A., & Poon, R. Y. C. (2004) · Cell Cycle · doi:10.4161/cc.3.9.1089 · Cited by 11
A new model and precious tool to study molecular mechanisms of macrophage aging
Smith, R., Bassand, K., Dussol, A., Piesse, C., Duplus, E., & Hadri, K. E. (2024) · Aging · doi:10.18632/aging.206124 · Cited by 20
“These results suggest that, in our model, macrophages exhibit a new senescent-like phenotype induced by in vitro culture conditions rather than induced by a senescent cell environment [73, 74].”
ResultA new insight into cell biological and biochemical changes through aging
Sahabi, S., Jafari-Gharabaghlou, D., & Zarghami, N. (2022) · Acta Histochemica · doi:10.1016/j.acthis.2021.151841 · Cited by 16
Graham, M. K., Principessa, L., Antony, L., Meeker, A. K., & Isaacs, J. T. (2016) · The Prostate · doi:10.1002/pros.23276 · Cited by 14
“Previous studies in keratinocytes and HMECs have demonstrated that co-culture with fibroblast feeder layers suppresses stress-induced senescence; thus permitting immortalization by TERT before p16 levels significantly increase [32,39].”
Regeneration of kidney tissue using in vitro cultured fetal kidney cells
Kim, S. S., Gwak, S., Han, J., Park, M. H., Song, K. W., & Kim, B. (2008) · Experimental & Molecular Medicine · doi:10.3858/emm.2008.40.4.361 · Cited by 15
“It has been reported that inadequate cell growth conditions may lead to premature growth arrest (Ramirez et al., 2001).”
BackgroundGire, V. (2005) · médecine/sciences · doi:10.1051/medsci/2005215491 · Cited by 37
Role of Senescence in Tumorigenesis and Anticancer Therapy
Stoczyńska-Fidelus, E., Węgierska, M., Kierasińska, A., Ciunowicz, D., & Rieske, P. (2022) · Journal of Oncology · doi:10.1155/2022/5969536 · Cited by 15
“Some human epithelial cells senesce with relatively long telomeres and high expression of p16, showing that p16 can inhibit cell proliferation through a mechanism other than TP53 [175, 176].”
BackgroundSmith, J. L., Lee, L. C., Read, A., Li, Q., Yu, B., Lee, C.-S., & Luo, J. (2016) · Cell & Bioscience · doi:10.1186/s13578-016-0122-6 · Cited by 15
“When grown in chemically defined media without feeder cells, primary human epithelial cells undergo rapid senescence that is likely a result of cell culture stress [2].”
BackgroundPhenotypic plasticity in normal breast derived epithelial cells
Sauder, C. A. M., Koziel, J. E., Choi, M.-R., Fox, M. J., Grimes, B. R., Badve, S., Blosser, R. J., Radovich, M., Lam, C. C., Vaughan, M. B., et al. (2014) · BMC Cell Biology · doi:10.1186/1471-2121-15-20 · Cited by 12
“Culture continued for 2 days submerged in keratinocyte medium [24] with 20 μg/ml ascorbic acid (SigmaAldrich, St.”
Self-citationCremona, C. A., & Lloyd, A. C. (2009) · Journal of Cell Science · doi:10.1242/jcs.047126 · Cited by 14
Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile
Minty, F., Thurlow, J. K., HARRISON, P., & Parkinson, E. K. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.05.007 · Cited by 16
Ways for a Mesenchymal Stem Cell to Live on Its Own: Maintaining an Undifferentiated State Ex Vivo
Toyoda, M., Takahashi, H., & Umezawa, A. (2007) · International journal of hematology · doi:10.1532/ijh97.07055 · Cited by 14
“Growth factor‐dependent acceleration of premature senescence or growth arrest is rather unexpected and unfavorable and is analogous to pressing down on the gas and brake pedals simultaneously [ 30 ,31].”
BackgroundMarques, M. M., Thomson, A., McCreath, K., & Mcwhir, J. (2006) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2006.03.009 · Cited by 14
Cancer and the Cellular Response to Hypoxia
Adamaki, M., Georgountzou, A., & Moschovi, M. (2013) · doi:10.4172/2161-0665.s1-002 · Cited by 14
Nontraditional systems in aging research: an update
Mikuła‐Pietrasik, J., Pakuła, M., Markowska, M., Uruski, P., Szczepaniak‐Chicheł, L., Tykarski, A., & Książek, K. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03658-w · Cited by 15
Islam, M. Q., Ringe, J., Reichmann, E., Migotti, R., Sittinger, M., Meirelles, L. D. S., Nardi, N., Magnusson, P., & Islam, K. (2006) · Cell and Tissue Research · doi:10.1007/s00441-006-0224-2 · Cited by 12
“Although mammalian somatic cells under standard cell culture conditions do not proliferate indefinitely, several independent reports indicate that normal cells can be grown for extended periods under improved cell culture conditions (Loo et al. 1987; Mathon et al. 2001; Ramirez et al. 2001; Romanov et al. 2001; Tang e…”
BackgroundTelomerase: diagnostics, cancer therapeutics and tissue engineering
Ouellette, M. M., & Lee, K. (2001) · Drug Discovery Today · doi:10.1016/s1359-6446(01)02052-9 · Cited by 13
The INK4a/ARF Locus and Human Cancer
Enders, G. H. (2003) · Humana Press eBooks · doi:10.1385/1-59259-328-3:197 · Cited by 10
Absence of premature senescence in Werner's syndrome keratinocytes
Ibrahim, B., Sheerin, A. N. P., Jennert‐Burston, K., Bird, J. L. E., Masala, M. V., Illsley, M. J., James, S. E., & Faragher, R. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.07.017 · Cited by 14
“If functional p16 is present within keratinocytes then growing the cells on plastic alone in keratinocyte serum freemedium is known to induce growth arrest (Ramirez et al., 2001).”
BackgroundMoon, S. C., Park, S. C., Yeo, E. J., & Kwak, C. S. (2009) · Journal of Medicinal Food · doi:10.1089/jmf.2008.1111 · Cited by 10
Gire, V. (2005) · doi:10.7202/010957ar · Cited by 11
“Cultivés dans des conditions adéquates, c’est-à-dire en présence de cellules nourricières, les kératinocytes peuvent être immortalisés par l’expression de hTERT seule [40].”
Telomeres and telomerase in normal and leukemic hematopoietic cells
Engelhardt, M. M., Wäsch, R., & Guo, Y. (2004) · Leukemia Research · doi:10.1016/j.leukres.2004.01.015 · Cited by 12
“Reintroduction of the catalytic component of telomerase into telomerase-negative human fibroblast and endothelial cells elongates telomeres and induces an increase of the replicative lifespan [11,12].”
BackgroundIdentification of a ≦600-kb region on human chromosome 1q42.3 inducing cellular senescence
Yawata, T., Kamino, H., Kugoh, H., Katoh, M., Nomura, N., Oishi, M., Horikawa, I., Barrett, J., & Oshimura, M. (2003) · Oncogene · doi:10.1038/sj.onc.1206143 · Cited by 10
Analysis of Tumor Suppressor Gene-Induced Senescence
Campisi, J. (2003) · Humana Press eBooks · doi:10.1385/1-59259-329-1:155 · Cited by 9
Sun, C., Huang, Z., Qin, H., Zhang, J., Wang, S., Xu, X., Ying, S., & Mao, G. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.761069 · Cited by 10
Horn, I. P., Marks, D. L., Koenig, A. N., Hogenson, T. L., Almada, L. L., Goldstein, L. E., Romecín, P. A., Vera, R. E., Vrabel, A. M., Cui, G., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100634 · Cited by 17
“Challenging cells with nutrient depletion is reported to increase p16 protein expression in fibroblasts (31, 32).”
BackgroundCytogenetic features of human trophoblast cell lines SWAN-71 and 3A-subE.
Reiter, J., Drendel, H. M., Chakraborty, S., Schellinger, M., Lee, M., & Mor, G. (2017) · Placenta · doi:10.1016/j.placenta.2017.02.010 · Cited by 9
Feijoo, P., Terradas, M., Soler, D., Domínguez, D., Tusell, L., & Genescà, A. (2016) · Breast Cancer Research · doi:10.1186/s13058-015-0667-z · Cited by 9
“few weeks of in vitro propagation [12, 13] that is associated with increased expression of the tumor suppressor p16.”
BackgroundThe Role of Chromatin Reorganization in the Process of Cellular Senescence
Tominaga, K., & Pereira‐Smith, O. M. (2012) · Current Drug Targets · doi:10.2174/138945012803529983 · Cited by 8
Hornsby, P. J. (2009) · Springer eBooks · doi:10.1007/978-1-4419-1075-2_4 · Cited by 7
“While p16 is elevated in cells in response to specific causes of damage, additionally p16 is often elevated in cells in culture, for largely unknown reasons (Ramirez et al. 2001; Parrinello et al. 2003; Herbig et al. 2004; Herbig and Sedivy 2006).”
BackgroundSherwood, A., Mutsaers, S., Peeva, V. K., Robinson, C., deSilva, C., Swanson, N., & Lake, R. (2008) · Cell Proliferation · doi:10.1111/j.1365-2184.2008.00560.x · Cited by 9
“Senescing cells in these cultures are likely to be the result of telomere-independent replicative senescence that is thought to be due to culture of cells in suboptimal conditions (Ramirez et al. 2001).”
BackgroundTamariz, E., Hernández-Quintero, M., Sánchez‐Guzmán, E., Arguello, C., & Castro-Muñozledo, F. (2007) · Archives of Medical Research · doi:10.1016/j.arcmed.2006.10.002 · Cited by 9
Spontaneous senescence in the MDA‐MB‐231 cell line
Ćukušić, A., Ivanković, M., Vidaček, N. Š., Kiš, M. F., Gotić, I., Matijašić, M., Polančec, D., & Rubelj, I. (2006) · Cell Proliferation · doi:10.1111/j.1365-2184.2006.00383.x · Cited by 9
“It is known that some normal and immortal cell lines respond to various forms of stress by positive SA-β-Gal activity (Robles & Adami 1998; Roninson 2003), called stress-associated β-Gal (Ramirez et al. 2001).”
BackgroundSenescence, Telomere Shortening and Telomere Maintenance
Hahn, W. (2002) · Cancer Biology & Therapy · doi:10.4161/cbt.1.4.14 · Cited by 9
Giri, S., & Bader, A. (2014) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2014.08.001 · Cited by 8
Kim, J., Eskiocak, U., Stadler, G., Lou, Z., Kuro-o, M., Shay, J., & Wright, W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.267641 · Cited by 8
Self-citationIs cellular senescence important in pediatric kidney disease?
Jacobi, C., Hömme, M., & Melk, A. (2011) · Pediatric Nephrology · doi:10.1007/s00467-010-1740-6 · Cited by 7
Gomes, N. M. V., Shay, J. W., & Wright, W. E. (2009) · Springer eBooks · doi:10.1007/978-90-481-3465-6_11 · Cited by 20
“Human skin keratinocytes grown in defined media suffered from p16/RB mediated growth arrest but this could be prevented growing cells on appropriate feeder layers [141].”
BackgroundSelf-citationIn vitro aging of rat lung cells
Petitot, F., Lebeau, J., Dano, L., Lectard, B., Altmeyer, S., Levalois, C., & Chevillard, S. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00103-4 · Cited by 7
The INK4A/Arf Network — Cell Cycle Checkpoint or Emergency Brake?
del Arroyo, A. G., & Peters, G. G. (2005) · Advances in experimental medicine and biology · doi:10.1007/1-4020-3764-3_8 · Cited by 8
“Although in some cases the stress response can be alleviated by optimising the culture conditions (Ramirez et al., 2001), these cells will not be immortalised by hTERT unless the arrest mechanism is turned off or over-ridden (Dickson et al.”
BackgroundWang, Y., Wong, M. M.-K., Zhang, X., & Chiu, S.-K. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.09.013 · Cited by 9
Augert, A., & Bernar, D. (2013) · InTech eBooks · doi:10.5772/55519 · Cited by 6
“It can be induced in response to additional inadequate culturing conditions such as abnormal growth factors, the absence of neighbour cells and extracellular matrix components and inadequate concentrations of nutrients, [45, 65, 66].”
BackgroundLong-term maintenance of human keratinocytes in vitro.
Hasskarl, J., Velupillai, P., Piboonniyom, S.-O., Grace, M., & Münger, K. (2005) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.23574.x · Cited by 7
Exploring cellular senescence as a tumor suppressor mechanism
Carnero, A., Blanco‐Aparicio, C., Blanco, F., Castro, M. E., Guijarro, M. V., Fominaya, J. M., Link, W., Martínez, J. F., Moneo, V., Renner, O., et al. (2003) · Revista de Oncología · doi:10.1007/bf02711481 · Cited by 6
An integrative review of nonobvious puzzles of cellular and molecular cardiooncology
Uruski, P., Matuszewska, J., Leśniewska, A., Rychlewski, D., Niklas, A. A., Mikuła‐Pietrasik, J., Tykarski, A., & Książek, K. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00451-y · Cited by 9
“A simultaneous upregulation of p16 and p21 in the irradiated, senescent ECs [72, 76] implies that both telomere-dependent [77] and telomere-independent [78] types of senescence machinery are involved.”
BackgroundGrayson, A. K., Hearnden, V., Bolt, R., Jebreel, A., Colley, H., & Murdoch, C. (2018) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2590 · Cited by 6
“, 2008) and stable elevated expression of hTERT (Dickson et al., 2000; Ramirez et al., 2001; Reijnders et al., 2015).”
BackgroundMethodPanyukhin, N. V., Vishnyakova, K. S., & Yegorov, Y. (2008) · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology · doi:10.1134/s1990747808040053 · Cited by 6
“and other cells are subject to so-called premature senescence in the course of their growth [22].”
BackgroundIslam, M. Q., Islam, K., & Sharp, C. A. (2007) · Stem Cells and Development · doi:10.1089/scd.2006.0094 · Cited by 6
“Other lines of investigation suggest that improved cell culture conditions avoid replicative senescence in normal cells, resulting in the generation of cell lines that proliferate in the long-term (82–86).”
Telomerization of mammalian cells and transplantation of telomerized cells in immunodeficient mice.
Hornsby, P. (2004) · Methods in molecular biology · doi:10.1385/1-59259-434-4:147 · Cited by 6
Passanisi, V. J., & Spencer, S. L. (2026) · iScience · doi:10.1016/j.isci.2026.114801 · Cited by 6
“79 40 However, in our experiments, telomere length metrics and telomere dysfunction measurements did not predict senescence even at low oxygen.”
Takahashi, H., Toyoda, M., Birumachi, J., Horie, A., Uyama, T., Miyado, K., Matsumoto, K., Saito, H., & Umezawa, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21860 · Cited by 5
“…expression in the LS medium In light of the fact that chemically defined growth medium containing growth factor(s) induces premature growth arrest of foreskin fibroblasts (Ramirez et al., 2001), we investigated the life span and p16ink4a induction of MF cells cultivated in LS growth medium (Fig.”
BackgroundResearch Article: Beta-galactosidase staining as a marker of cells enduring stress
Wood, M., & Cavender, J. F. (2004) · BIOS · doi:10.1893/0005-3155(2004)075 · Cited by 5
Model Organisms for Studying the Cell Cycle
Tang, Z. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2957-3_2 · Cited by 5
Azyenela, R., Julianto, I., & Wirohadidjojo, Y. (2018) · Malaysian Journal of Medical and Biological Research · doi:10.18034/mjmbr.v5i2.456 · Cited by 4
“This treatment resembled previous studies (Alcorta et al., 1996 and Ramirez et al., 2001).”
ResultOncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells
Dellambra, E. (2016) · Small GTPases · doi:10.1080/21541248.2016.1182242 · Cited by 4
“Oxidative stress and nutrient deprivation induce a Bmi-1 mediated p16 increase and premature senescence accompanied by an abrupt onset of clonal conversion in primary human keratinocytes.(3,8,21)”
BackgroundDevelopment and characterization of a new human hepatic cell line
Ramboer, E., Craene, B. D., Kock, J. D., Berx, G., Rogiers, V., Vanhaecke, T., & Vinken, M. (2015) · EXCLI journal · doi:10.17179/excli2015-424 · Cited by 4
“…premature growth arrest observed in several epithelial cells might be partially involved in the limited proliferation capacity of adult hepatocytes in vitro (Auer et al., 1998; Tombes et al., 1998; Ramirez et al., 2001, 2003; Ohtani et al., 2004; Harashima et al., 2013; Ramboer et al., 2014).”
BackgroundSenescence and Senescence-Related Disorders
Wang, Z. P., & Inuzuka, H. (2013) · InTech eBooks · doi:10.5772/56158 · Cited by 12
Jovov, B., Orlando, G. S., Tobey, N. A., Brown, K., Djukic, Z., Carson, J., Brighton, L., & Orlando, R. (2009) · Diseases of the esophagus · doi:10.1111/j.1442-2050.2008.00907.x · Cited by 4
Familial Melanoma Genes, Melanocyte Immortalization, and Melanoma Initiation
Bennett, D. C. (2007) · Humana Press eBooks · doi:10.1007/978-1-59259-994-3_10 · Cited by 5
Kim, K.-W., Jeong, S.-W., Park, H., Heu, J.-Y., Jung, H., & Lee, J.-S. (2020) · Biotechnic & Histochemistry · doi:10.1080/10520295.2020.1721560 · Cited by 3
Ohtani, N., Yamakoshi, K., Takahashi, A., & Hara, E. (2010) · Cell Division · doi:10.1186/1747-1028-5-1 · Cited by 62
“ing on the cell culture conditions[20-23], it remains unclear whether the induction of p16 gene expression in cultured human primary cells truly reflects an anti-cancer process or is an artifact of tissue cultureimposed stress.”
Telomere-Induced Senescence of Primary Cells
Allsopp, R. (2007) · Springer eBooks · doi:10.1007/978-3-540-73709-4_2 · Cited by 2
Immortalization of patient-derived lip cells for establishing 3D lip models
Mansour, F., Parisi, L., Rihs, S., Schnyder, I., Scala, G. L. L., Aliu, N., Katsaros, C., & Degen, M. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1449224 · Cited by 2
Cancer, Senescence, and Aging: Translation from Basic Research to Clinics
LLeonart, M. E., Carnero, A., Paciucci, R., Wang, Z., & Shomron, N. (2011) · Journal of Aging Research · doi:10.4061/2011/692301 · Cited by 1
“Importantly, LIN28 functions as an oncogene promoting malignant transformation and tumor progression [51].”
BackgroundIncreased in vitro lifespan of primary human keratinocytes correlates with decreased migration.
Hasskarl, J., Velupillai, P., & Münger, K. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700205 · Cited by 2
“P16INK4A plays an important role in the control of proliferation and stressinduced senescence and may represent a surrogate marker for TC stress (Zhu et al., 1998; Ramirez et al., 2001; Herbert et al., 2002; reviewed by Lundberg et al., 2000).”
BackgroundPro-senescence Therapy for Cancer: Time for the Clinic
Kalathur, M., Mitri, D. D., & Alimonti, A. (2014) · Springer eBooks · doi:10.1007/978-94-017-9421-3_8 · Cited by 2
The Secretome of Senescent Cells
Gowrishankar, B., & Adams, P. D. (2009) · Springer eBooks · doi:10.1007/978-1-4419-1075-2_5 · Cited by 2
Ramirez, R. D. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-221-2_8
Self-citationTelomeric Shortening and Replicative Aging
Wright, W. E., & Shay, J. W. (2003) · CRC Press eBooks · doi:10.1201/9780203911709.ch4 · Cited by 1
Self-citationSuppression of genomic instability by replicative senescence and crisis
Karlseder, J. (2020) · Genome Instability & Disease · doi:10.1007/s42764-020-00013-y · Cited by 4
Papillomavirus infection and telomerase activation
Allen, H. K., & Klingelhutz, A. J. (2003) · Papillomavirus Report · doi:10.1179/095741903225001598 · Cited by 1
Darbro, B. W. (2007) · doi:10.17077/etd.2qnj4kik · Cited by 1
“When grown in co-culture with post-mitotic fibroblast feeder cells, many epithelial cell types, including human keratinocytes, exhibit a delay in passage dependent p16 expression and have an extended lifespan in culture (Baek et al., 2003; Darbro et al., 2005; Fu et al., 2003; Herbert et al., 2002; Kang et al., 2003;…”
BackgroundResultInfluentialContributions of Telomerase to Tumorigenesis
Possemato, R., & Hahn, W. C. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-221-2_9
Replicative Senescence, Telomeres and Werner’s Syndrome
Faragher, R. (2004) · Springer eBooks · doi:10.1007/978-1-4419-9032-7_9 · Cited by 1
Toouli, C. D., & Reddel, R. R. (2003) · Springer eBooks · doi:10.1007/978-94-017-0669-8_10 · Cited by 1
The Relationship Between Cell Turnover and Tissue Aging
Faragher, R. (2003) · Springer eBooks · doi:10.1007/978-94-017-0673-5_1 · Cited by 1
Role of HSP72 in alleviating heat stress-induced damage in Sertoli cells of dairy bulls
Zhang, H.-D., Xie, L., Wang, H.-Y., Yan, X.-Y., Chen, H., Wei, Y.-X., Geng, Z.-H., Zhu, S.-Y., Jiang, Z.-L., Li, H.-T., et al. (2026) · Histochemistry and Cell Biology · doi:10.1007/s00418-026-02541-2
“Ideal growth conditions are fundamental for maintaining normal cell development and function; adverse growth conditions severely inhibit cell proliferation and even cause cell death (Ramirez et al. 2001; Soti et al. 2003).”
From Primary Cells to Organoids: Expanding the Biological Relevance of In Vitro Cellular Models
Deng, F., Wang, Y., Castellano, L. A., & Zhao, C. (2026) · Cells · doi:10.3390/cells15191741
“In many cases, combinatorial strategies, such as TERT combined with CDK4 or HPV E6/E7, provide higher immortalization efficiency and improved long-term proliferation across diverse cell types [22,24,41,47].”
In vitro alternatives to animal models for the assessment of nanoparticle respiratory toxicity
McAllister, K., Brooks, S., Clift, M. J. D., & Murphy, F. (2026) · Nanomedicine · doi:10.1080/17435889.2026.2698783
Liu, S., Wang, Z., Cao, H.-R., Tong, J., Cui, J., Li, L., Bu, Q., Li, Y., Jin, T., An, X.-P., et al. (2024) · Journal of Food Science · doi:10.1111/1750-3841.17370
[Sorting of senescent cells by flow cytometry: Specificities and pitfalls to avoid].
Rodzinski, É., Martin, N., Rouget, R., Pioger, A., Dehennaut, V., Molendi-Coste, O., Dombrowicz, D., Goy, E., de Launoit, Y., & Abbadie, C. (2024) · Medecine sciences : M/S · doi:10.1051/medsci/2024011
Investigating the Molecular Carcinogenesis of Ovarian High-Grade Serous Carcinoma
Kyo, S. (2021) · Current human cell research and applications · doi:10.1007/978-981-33-6013-6_4
Premature Senescence In Primary Glioblastoma Cells
Kumar, R. (2018) · doi:10.20381/ruor-22192
The effects of laser immunotherapy on cancer cell migration
Bahavar, C. F., Zhou, F.-F., Hasanjee, A. M., Layton, E., Lam, A. K., Chen, W. R., & Vaughan, M. (2016) · BiOS · doi:10.1117/12.2216592
Neumayer, B. (2015) · doi:10.15496/publikation-7458
“Senescence is also induced by oncogenes such as H-RasV12 when DNA damage is recognised [158, 159].”
BackgroundThe Cellular Senescence Program
Shivshankar, P., & Saux, C. J. L. (2014) · Wiley eBooks · doi:10.1002/9781118396292.ch5
Translational Control of Cell Proliferation and Viability in Normal and Neoplastic Cells
Avdulov, S. V., Gómez-García, J. R., Bitterman, P. B., & Polunovsky, V. A. (2014) · Springer eBooks · doi:10.1007/978-94-017-9078-9_18
Heterogeneous activation of p19Arf in pulmonary artery smooth muscle cells.
Solodushko, V., Alvarez, D., Viator, R., Messerall, T., & Fouty, B. (2011) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00117.2010
Lodygin, D. (2005) · Electronic Theses of LMU Munich (Ludwig-Maximilians-Universität München) · doi:10.5282/edoc.4361
View of a young biogerontologist on the in vitro biogerontological model systems.
Toussaint, O. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.002
Telomerase: Key to Mortal or Immortal Road
Yang, E.-Y., Sung, Y. H., & Lee, H.-W. (2002) · Immune Network · doi:10.4110/in.2002.2.4.183
“In other words, human keratinocytes grown on appropriate feeder layers could directly immortalized by hTERT maintenance of telomeres without any intervening inactivation of a p16/pRB pathway (45,46).”
BackgroundGatinois, V. (2020) · doi:10.70675/5688e521z608dz45c3z950czef3ee5b3116e
“Rapidement, ce phénomène a été identifié dans d’autres types de cancer, comme les cancers colorectaux [6] et prostatiques [7], les myélomes [8], les neuroblastomes [9] et les lymphomes de Hodgkin [10].”
BackgroundStochastic Nature of Cellular Aging: The Role of Telomeres
Vidaček, N. Š., & Rubelj, I. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11457-6
Premature senescence of mesenchymal stem cells: causes and preventive measures
Zhou, L., He, F., & Wang, L. (2018) · doi:10.3969/j.issn.2095-4344.0632
Ross, A. L., Sanchez, M. I., & Grichnik, J. M. (2012) · Springer eBooks · doi:10.1007/978-3-642-28397-0_10
Visualizing the dynamics of senescence stress response in living animals
Yamakoshi, K., & Hara, E. (2012) · Inflammation and Regeneration · doi:10.2492/inflammregen.32.032
Antagonistic Pleiotropy: The Role of Smurf2 in Cancer and Aging: A Dissertation
Ramkumar, C. (2012) · eScholarship@UMassChan · doi:10.13028/b1er-s046
“The expression of p16 is readily increased during premature senescence induced by a variety of stressors [30,32,33,38].”
BackgroundRegulatory mechanisms governing mammary epithelial and progenitor cell growth
Burleigh, A. (2011) · doi:10.14288/1.0071902
“41 the in vitro culture conditions and is not required for eventual cellular immortalization [181, 182].”
BackgroundChromatin in Senescent Cells: A Conduit for the Anti-Aging Effects of Wnt Signaling?
Gowrishankar, B., & Adams, P. D. (2009) · Springer eBooks · doi:10.1007/978-1-4419-0639-7_6
“in vitro growth conditions, and other cellular stresses (Campisi, 2005; Herbig and Sedivy, 2006; Ramirez et al., 2001; Wright and Shay, 2002).”
Background
Metadata
- 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)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
