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Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation
Abstract
Aberrations affecting the tumor suppressor gene p16INK4a have been described for a variety of tumors. In breast cancer, approximately 50% of tumors show low or lack p16 expression. While evidence provided by some studies has implicated a possible role for p16 in normal replicative senescence, other studies have suggested that the Rb, pathway through which p16 functions, may not be involved in senescence control. Previously we observed that all immortal lines derived from normal mammary epithelium which were analysed for p16 displayed inactivation of this gene through distinct mechanisms, supporting p16 inactivation as a possible necessary event in escape from senescence. To further clarify this issue, we have analysed p16 expression in a panel of normal finite lifespan human mammary epithelial cells (HMEC) from initial propagation through growth arrest, using media which confer different replicative capacity. Approximately 10-25-fold increase in p16 expression was observed for all normal HMEC with initial onset of a senescence phenotype following 15-25 population doublings in culture. These cells also displayed expression of the senescence associated beta-galactosidase. Interestingly, HMEC with additional long term replicative capacity (approximately 80 population doublings) arose from these growth arrested cultures, showing lack of p16 expression. This extended growth capacity appears to be associated with a methylation phenomenon since treatment of these cells with the methylation inhibitor 5-aza-2-deoxycytidine resulted in growth arrest concurrent with reacquisition of p16 expression and senescence associated beta-galactosidase. Analysis of p21waf1 expression revealed no change in expression during growth in vitro. These results support p16INK4a as the 9p senescence gene and suggest a role for p16 loss in the escape from initial onset of senescence and in acquisition of an extended life span of human mammary epithelial cells.
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“Primary human fibroblasts and epithelial cells also express increasing levels of p16 during culture (Reznikoff et al., 1996; Brenner et al., 1998; Rheinwald et al., 2002; Benanti and Galloway, 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Brenner et al., 1998
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Duan, J., Zhang, Z., & Tong, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104814200 · Cited by 63
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Meadows, A. L., Kong, B., Berdichevsky, M., Roy, S., Rosiva, R., Blanch, H. W., & Clark, D. S. (2008) · Biotechnology Progress · doi:10.1021/bp070301d · Cited by 62
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BackgroundMechanisms of Traditional Chinese Medicine in the Treatment of Mammary Gland Hyperplasia
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Primary Cilium-Dependent and -Independent Hedgehog Signaling Inhibits p16INK4A
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Self-citationEscape from senescence: molecular basis and therapeutic ramifications
Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023) · The Journal of Pathology · doi:10.1002/path.6164 · Cited by 57
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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
Culture Models of Human Mammary Epithelial Cell Transformation
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Self-citationHerbert, B., Wright, A., Passons, C., Wright, W. E., Ali, I., Kopelovich, L., & Shay, J. W. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.1.39 · Cited by 51
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
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BackgroundResultInfluentialTRIM24 links glucose metabolism with transformation of human mammary epithelial cells
Pathiraja, T. N., Thakkar, K. N., Jiang, S., Stratton, S. A., Liu, Z., Gagea, M., Shi, X., Shah, P. K., Phan, L. M., Lee, M.-H., et al. (2014) · Oncogene · doi:10.1038/onc.2014.220 · Cited by 52
Self-citationCpG Island Tumor Suppressor Promoter Methylation in Non-BRCA-Associated Early Mammary Carcinogenesis
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“Women enrolled in study 109 Bilateral RPFNA 84 Unilateral RPFNA 25 RPFNA samples collected 193 Average age (range), y 47 (29-65) Race, n (%) Caucasian 98 (90) African American 11 (10) Menopausal status, n (%) Post/perimenopausal 44 (40) Premenopausal 65 (60) Hormone replacement use, n (%) Current 0 (0) Ever use 13 (12…”
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“In the serum-containing medium, MM, the HMEC population ceases active growth after approximately 15 ± 25 Pd, coincident with expression of high levels of p16 (Stampfer, 1982, 1985; Brenner et al., 1998).”
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“Spontaneous karyoplast budding and EL cell growths were photographed in live cultures (Walen, 2004), and similar spontaneous occurrence of EL cells in senescent human mammary epithelial cell cultures (HMEC) was found to have genome changes (Brenner et al., 1998; Huschtscha et al., 1998; Romanov et al., 2001).”
BackgroundBean, G. R., Bryson, A. D., Pilie, P. G., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0407 · Cited by 48
“p16 33% (4) 12% (3) 18% (3) RARB M3 83% (10) 68% (17) 71% (15) RARB M4 25% (3) 24% (6) 35% (6) ESR1 0% (0) 7% (7) 41% (7) BRCA1 6% (1) 20% (5) 24% (4)”
BackgroundConstructing immortalized human cell lines
Yeager, T. R., & Reddel, R. R. (1999) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(99)00011-7 · Cited by 47
The paradox of senescent-marker positive cancer cells: challenges and opportunities
O’Sullivan, E. A., Wallis, R., Mossa, F., & Bishop, C. L. (2024) · npj Aging · doi:10.1038/s41514-024-00168-y · Cited by 50
“However, through hypermethylation of the p16 promoter, ~1 in 10 4 cells can escape this process and re-enter the cell cycle, before entering a stable p21-dependent senescence programme following replicative exhaustion 20,21 .”
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“HMEC can spontaneously overcome a first RB-mediated, non-telomere length dependent proliferative arrest (stasis), associated with down-regulation of p16 expression (Brenner et al., 1998).”
BackgroundSelf-citationCYCLOSPORINE INDUCES THE EXPRESSION OF THE CYCLIN INHIBITOR p21
Khanna, A. K., & Hosenpud, J. D. (1999) · Transplantation · doi:10.1097/00007890-199905150-00011 · Cited by 44
Jensen, T. J., Novák, P., Wnek, S. M., Gandolfi, A. J., & Futscher, B. W. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.08.019 · Cited by 46
“Early in tumorigenesis, epithelial cells go through distinct proliferative barriers that must be overcome prior to reaching immortality (Brenner et al., 1998; Romanov et al., 2001; Stampfer and Yaswen, 2003; Garbe et al., 2007).”
Loss of Chromosomal Integrity in Human Mammary Epithelial Cells Subsequent to Escape from Senescence
Tlsty, T. D., Romanov, S. R., Kozakiewicz, B. K., Holst, C. R., Haupt, L. M., & Crawford, Y. (2001) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/a:1011369026168 · Cited by 47
Senescence and immortalization of human cells
Duncan, E. L., Wadhwa, R., & Kaul, S. C. (2000) · Biogerontology · doi:10.1023/a:1010000132671 · Cited by 46
“Spontaneous loss of p16INK4 expression is associated with lifespan extension in mammary epithelial cells (Brenner et al. 1998; Huschtscha et al. 1998).”
BackgroundRatsch, S. B., Gao, Q., Srinivasan, S. V., Wazer, D. E., & Band, V. (2001) · Radiation Research · doi:10.1667/0033-7587(2001)155[0143:mgcarf]2.0.co;2 · Cited by 44
CRISPR-Cas System: The Current and Emerging Translational Landscape
Bhokisham, N., Laudermilch, E., Traeger, L. L., Bonilla, T. D., Ruíz-Estévez, M., & Becker, J. R. (2023) · Cells · doi:10.3390/cells12081103 · Cited by 46
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“Normal human mammary epithelial cells (HMECs) are known to undergo p16-mediated cellular senescence, independent of telomere attrition [8, 9].”
BackgroundSelf-citationCDK2 translational down-regulation during endothelial senescence
Freedman, D. A., & Folkman, J. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.03.025 · Cited by 44
Kim, Y., Jung, J. K., Lee, S. Y., & Jang, K. L. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.07.007 · Cited by 41
“The p16 protein has been noted to be a key determinant of cellular senescence in a variety of human cell types [12,13].”
BackgroundDarbro, B. W., Schneider, G. B., & Klingelhutz, A. J. (2005) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2005.23844.x · Cited by 42
“…senescence or growth arrest, termed cellular stasis, that cannot be overcome by maintaining telomere length alone (Foster and Galloway, 1996;Brenner et al, 1998;Kiyono et al, 1998;Jarrard et al, 1999;Puthenveettil et al, 1999;Dickson et al, 2000;Sandhu et al, 2000;Stampfer and Yaswen,…”
Backgroundp53-dependent integration of telomere and growth factor deprivation signals
Beliveau, A., Bassett, E., Lo, A. T., Garbe, J. C., Rubio, M. Á., Bissell, M. J., Campisi, J., & Yaswen, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700260104 · Cited by 38
Sherman, M. Y., Le, M., Stampfer, M. R., Gabai, V. L., & Yaglom, J. A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00736.x · Cited by 39
“…cells, which were obtained by ectopic expression of hTERT in 184 HMEC, and (ii) 184BTERT cells which were obtained by the expression of recombinant hTERT in 184 HMEC line that spontaneously lost p16 because of promoter methylation (Brenner et al., 1998; Stampfer et al., 2001; Garbe et al., 2009).”
MethodSelf-citationSeverson, P. L., Vrba, L., Stampfer, M. R., & Futscher, B. W. (2014) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2014.10.011 · Cited by 37
“The first barrier, termed stasis or stress-induced senescence, is characterized by elevated levels of the cyclin-dependent kinase inhibitor p16INK4A (gene CDKN2A) maintaining the retinoblastoma protein (RB) in an active state [11,13,18].”
InfluentialSelf-citationSaleh, T., Alhesa, A., Al-Balas, M., Abuelaish, O. M., Mansour, A. T., Awad, H., El‐Sadoni, M., Carpenter, V. J., & Azab, B. (2021) · Bioscience Reports · doi:10.1042/bsr20210079 · Cited by 39
“…of the senescent growth arrest is enforced by the activation of several cell cycle-regulating proteins [21], including cyclin-dependent kinase inhibitors (CDKIs) such as p21 CIP1 or p16 INK4a [22,23]. p21 CIP1 mediates the growth arrest occurring in replicative exhaustion-induced senescence [24].”
Gao, J., Wang, H. L., Shreve, A. P., & Iyer, R. S. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.12.025 · Cited by 40
Predicting functional significance of cancer-associated p16INK4a mutations in CDKN2A
McKenzie, H. A., Fung, C., Becker, T. M., Irvine, M., Mann, G. J., Kefford, R. F., & Rizos, H. (2010) · Human Mutation · doi:10.1002/humu.21245 · Cited by 38
“The progressive accumulation of p16INK4a is also associated with the onset of replicative senescence [Alcorta et al., 1996; Brenner et al., 1998] and p16INK4a expression induces growth arrest that resembles cellular senescence in human cells [Haferkamp et al., 2008; McConnell et al., 1999; Zhu et…”
BackgroundEpigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis
Locke, W. J., & Clark, S. J. (2012) · Breast Cancer Research · doi:10.1186/bcr3237 · Cited by 36
D’Amico, M., Wu, K., Fu, M., Rao, M., Albanese, C., Russell, R. G., Lian, H., Bregman, D. B., White, M. A., & Pestell, R. G. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2519 · Cited by 38
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Pustavoitau, A., Barodka, V., Sharpless, N. E., Torrice, C., Nyhan, D., Berkowitz, D. E., Shah, A. S., Bandeen Roche, K. J., & Walston, J. D. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2015.12.003 · Cited by 36
“Expression of p16 is not detected in young cells, but is potently activated by stress factors that promote cellular senescence (Brenner et al., 1998; te Poele et al., 2002; Kim and Sharpless, 2006; Song et al., 2010).”
Connecting cancer relapse with senescence
Pluquet, O., Abbadie, C., & Coqueret, O. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.08.004 · Cited by 38
Locke, W. J., Zotenko, E., Stirzaker, C., Robinson, M. D., Hinshelwood, R. A., Stone, A. M., Reddel, R. R., Huschtscha, L. I., & Clark, S. J. (2015) · Clinical Epigenetics · doi:10.1186/s13148-015-0086-0 · Cited by 34
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BackgroundKan, C. E., Cipriano, R., & Jackson, M. W. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3860 · Cited by 34
Shachar, S. S., Deal, A. M., Reeder-Hayes, K. E., Nyrop, K. A., Mitin, N., Anders, C. K., Carey, L., Dees, E. C., Jolly, T. A., Kimmick, G. G., et al. (2020) · JNCI Cancer Spectrum · doi:10.1093/jncics/pkaa082 · Cited by 33
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“Some cells, however, are subjected to a self-selection process triggered by hypermethylation of the p16 promotor and subsequent loss of p16 expression (Brenner et al., 1998; Huschtscha et al., 1998).”
Lee, J. K., Garbe, J. C., Vrba, L., Miyano, M., Futscher, B. W., Stampfer, M. R., & LaBarge, M. A. (2015) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2015.00013 · Cited by 31
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Darbro, B. W., Lee, K. M., Nguyen, N., Domann, F. E., & Klingelhutz, A. J. (2006) · Oncogene · doi:10.1038/sj.onc.1209729 · Cited by 32
“…(keratinocytes, mammary epithelial cells, bladder urothelial cells and prostatic epithelial cells), however, have been shown to experience a telomere-independent growth arrest that is enforced by the p16/pRb pathway (Foster and Galloway, 1996; Brenner et al., 1998; Puthenveettil et al., 1999).”
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“expression (8, 17, 22) and give rise to postselection cells.”
BackgroundAutophagy and senescence in cancer therapy
Patel, N. H., Bloukh, S., Alwohosh, E., Alhesa, A., Saleh, T., & Gewirtz, D. A. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.01.002 · Cited by 36
MMP-7 is involved in the aging of primary human mammary epithelial cells (HMEC)
Bertram, C., & Hass, R. (2007) · Experimental Gerontology · doi:10.1016/j.exger.2007.11.007 · Cited by 30
Junk, D. J., Cipriano, R., Stampfer, M. R., & Jackson, M. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053776 · Cited by 30
“However, when grown in the serum-free MCDB170 medium (commercial MEGM), rare post-selection cells emerge that no longer express p16 protein due to promoter methylation [7,8].”
BackgroundInfluentialSelf-citationDNA methylation of nuclear receptor genes—possible role in malignancy
Berger, J., & Daxenbichler, G. (2002) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(01)00179-0 · Cited by 29
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Self-citationAn Integrated Human Mammary Epithelial Cell Culture System for Studying Carcinogenesis and Aging
Stampfer, M. R., LaBarge, M. A., & Garbe, J. C. (2013) · Humana Press eBooks · doi:10.1007/978-1-62703-634-4_15 · Cited by 29
Self-citationCui, Y., Lu, C., Liu, L., Sun, D., Yao, N., Tan, S., Bai, S., & Ma, X. (2007) · Life Sciences · doi:10.1016/j.lfs.2007.11.013 · Cited by 29
“It has been proposed that loss of p16INK4A expression is required for cells to escape senescence during their progression to malignancy (Brenner, 1998).”
BackgroundGonzález‐Gil, C., Ribera, J., Ribera, J., & Genescà, E. (2021) · Genes · doi:10.3390/genes12010079 · Cited by 32
“These post-selected growing cells do not express CDKN2A mRNA and protein [146].”
BackgroundEl‐Sadoni, M., Shboul, S. A., Alhesa, A., Shahin, N. A., Alsharaiah, E., Ismail, M. A., Ababneh, N. A., Alotaibi, M. R., Azab, B., & Saleh, T. (2023) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-023-04523-w · Cited by 28
“TIS shares several features of the classical, aging-associated, replicative senescence, including enlarged, flattened morphology [3], growth arrest [4], induction of the DNA damage repair response [5–8], activation of cell cycle regulators such as p21Cip1 and p16INK4a [9, 10], polyploidy [11, 12], upregulation of the…”
BackgroundImmortalization and transformation of human mammary epithelial cells by a tumor-derived Myc mutant
Thibodeaux, C. A., Liu, X., Disbrow, G. L., Zhang, Y., Rone, J. D., Haddad, B. R., & Schlegel, R. (2008) · Breast Cancer Research and Treatment · doi:10.1007/s10549-008-0127-x · Cited by 28
“These HMECs are characterized by a loss of p16 expression caused by promoter methylation [5, 8, 9] and are referred to as post-selection HMECs.”
BackgroundRole of Gene Methylation in Antitumor Immune Response: Implication for Tumor Progression
Serrano, A., Castro-Vega, I., & Redondo, M. (2011) · Cancers · doi:10.3390/cancers3021672 · Cited by 28
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Self-citationMukhopadhyay, R., Costes, S. V., Bazarov, A. V., Hines, W. C., Barcellos‐Hoff, M. H., & Yaswen, P. (2010) · Breast Cancer Research · doi:10.1186/bcr2477 · Cited by 26
“The lack of p16 expression in unirradiated vHMEC has been associated with methylation of the p16 gene promoter, as treatment with 5-aza-2’-deoxycytidine - an established inhibitor of DNA methylation, leads to induction of p16 expression and growth arrest in these cells [23-25].”
BackgroundAutofluorescence-based sorting removes senescent cells from mesenchymal stromal cell cultures
Bertolo, A., Guerrero, J., & Stoyanov, J. V. (2020) · Scientific Reports · doi:10.1038/s41598-020-76202-2 · Cited by 27
Epigenetic Changes During Cell Transformation
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“The resultant post-stasis cells commonly show p16 inactivation by gene mutation or promoter hypermethylation [50, 54].”
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“184A1 cells were grown in MCDB170 media as previously described [29].”
MethodSelf-citationJokela, T. A., Engelsen, A. S. T., Rybicka, A. M., Vatter, F. A. P., Garbe, J. C., Miyano, M., Tiron, C. E., Ferariu, D., Akslen, L. A., Stampfer, M. R., et al. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00041 · Cited by 25
“Finite post-stasis 184Aa were derived following benzo-a-pyrene (BaP) exposure of pre-stasis 184, and lack expression of the CKI p16INK4a (Stampfer and Bartley, 1985; Brenner et al., 1998).”
BackgroundSelf-citationSenotherapeutics in Cancer and HIV
Sánchez-Díaz, L., Espinosa-Sánchez, A., Blanco, J. R., & Carnero, A. (2022) · Cells · doi:10.3390/cells11071222 · Cited by 27
Epigenetic targeting in breast cancer: Therapeutic impact and future direction
Lustberg, M. B., & Ramaswamy, B. (2009) · Drug News & Perspectives · doi:10.1358/dnp.2009.22.7.1405072 · Cited by 24
Zhou, R., Frum, R. A., Deb, S., & Deb, S. P. (2005) · Cancer Research · doi:10.1158/0008-5472.can-03-3755 · Cited by 24
“Consistent with the earlier reports, we could not detect p16 expression in commercially available passage 7 HMEC cells (47).”
ResultSavarese, T. M., Jang, T., Low, H. P., Salmonsen, R. A., Litofsky, N. S., Matijašević, Z., Ross, A. H., & Recht, L. D. (2005) · Journal of neurosurgery · doi:10.3171/jns.2005.102.1.0098 · Cited by 23
Wang, Y., Xu, Q., Sack, L. M., Kang, C., & Elledge, S. J. (2016) · Genes & Development · doi:10.1101/gad.271445.115 · Cited by 24
“For instance the Human Mammary Epithelial cells (HMEC) are very sensitive to the “culture shock” when maintained in vitro [57]; they upregulate p16 as a response and slow down proliferation without p53 activation, until clones that spontaneously silence p16 take over the population.”
BackgroundFukuda, T., Furuya, K., Takahashi, K., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101929 · Cited by 23
Cell-Type Specific DNA Methylation Patterns Define Human Breast Cellular Identity
Novák, P., Stampfer, M. R., Muñoz-Rodríguez, J. L., Garbe, J. C., Ehrich, M., Futscher, B. W., & Jensen, T. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052299 · Cited by 23
“that publication (Lonza-2551) are post-stasis HMEC that have overcome the stasis senescence barrier, associated with silencing of the p16 promoter [38–40].”
BackgroundSelf-citationShining the Light on Senescence Associated LncRNAs
Ghanam, A. R., Xu, Q., Ke, S., Azhar, M., Cheng, Q., & Song, X. (2017) · Aging and Disease · doi:10.14336/ad.2016.0810 · Cited by 23
The molecular signature of in vitro senescence in human mesenchymal stem cells
Noh, H. B., Ahn, H.-J., Lee, W., Kwack, K., & Kwon, Y. D. (2010) · Genes & Genomics · doi:10.1007/s13258-010-0868-x · Cited by 23
“telomere-independent premature senescence (Brenner et al., 1998; Ramirez et al., 2001; Itahana et al., 2003; Krishnamurthy et al., 2004).”
p16 INK 4a deficiency promotes DNA hyper‐replication and genetic instability in melanocytes
Fung, C., Pupo, G. M., Scolyer, R. A., Kefford, R. F., & Rizos, H. (2013) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12062 · Cited by 23
“The expression profile of p16INK4a also underscores its critical role as a tumour suppressor; p16INK4a accumulates progressively as cells near replica- tive senescence (Alcorta et al., 1996; Brenner et al., 1998) and in response to oncogenic signals (Serrano et al., 1997).”
BackgroundDungan, C. M., Wells, J. M., & Murach, K. A. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00553.2022 · Cited by 21
Cotarelo, C., Schad, A., Kirkpatrick, C. J., Sleeman, J. P., Springer, E., Schmidt, M., & Thaler, S. (2016) · Oncotarget · doi:10.18632/oncotarget.12432 · Cited by 22
Breindel, J. L., Skibinski, A., Sedic, M., Wronski, A., Zhou, W., Keller, P. J., Mills, J. E., Bradner, J. E., Önder, T. T., & Kuperwasser, C. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.06.019 · Cited by 21
“…from breast tissue rapidly undergoes Rb-mediated senescence after 5–10 population doublings Stem Cell Rep This is an open access article under the C (Brenner et al., 1998; Foster and Galloway, 1996); however, rare proliferative clones, called variant HMECs (vHMECs), invariably emerge from primary…”
BackgroundFurth, E. E., Gustafson, K. S., Dai, C. Y., Gibson, S. L., Menard-Katcher, P. A., Chen, T., Koh, J., & Enders, G. H. (2006) · Neoplasia · doi:10.1593/neo.06169 · Cited by 21
“Extensively passaged mammary epithelia cells typically sustain p16 promoter methylation [52] and serve as negative control ( C).”
Backgroundp16 gene therapy: a potentially efficacious modality for nasopharyngeal carcinoma.
Lee, A. W. C., Li, J., Shi, W., Li, A., Ng, E., Liu, T.-J., Klamut, H. J., & Liu, F. (2003) · PubMed · Cited by 18
Epigenetic mechanisms in senescence, immortalisation and cancer
Carnero, A., & LLeonart, M. E. (2010) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/j.1469-185x.2010.00154.x · Cited by 19
“Minimal epigenetic changes, such as aberrant DNA methylation, emerge as the earliest stages of HMEC transformation in the finite life span in vitro (Brenner et al., 1998).”
BackgroundSmith, S. K., & Kipling, D. (2004) · Cytogenetic and Genome Research · doi:10.1159/000078219 · Cited by 17
“Well-studied examples include human mammary epithelial cells (Foster and Galloway, 1996; Brenner et al., 1998; Huschtscha et al., 1998; Farwell et al., 2000), keratinocytes (Kiyono et al.”
BackgroundInfluentialp16 loss rescues functional decline of Brca1-deficient mammary stem cells
Scott, A., Bai, F., Chan, H. L., Liu, S., Slingerland, J. M., Robbins, D. J., Capobianco, A. J., & Pei, X. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1295185 · Cited by 18
“tion and enter a cell cycle arrest with increased expression of p16.(25) Furthermore, it has been demonstrated that spontaneous”
BackgroundCellular Senescence in Normal Mammary Gland and Breast Cancer. Implications for Cancer Therapy
Sirinian, C., Peroukidis, S., Kriegsmann, K., Chaniotis, D. I., Koutras, A. K., Kriegsmann, M., & Papanastasiou, A. D. (2022) · Genes · doi:10.3390/genes13060994 · Cited by 15
Suzuki, H. (2009) · International Journal of Oncology · doi:10.3892/ijo_00000206 · Cited by 16
The transcriptome of wild-type and immortalized corneal epithelial cells
Furuya, K., Wu, T., Orimoto, A., et al. (2021) · Scientific Data · doi:10.1038/s41597-021-00908-9 · Cited by 16
Induction of p16/INK4a Gene Expression and Cellular Senescence by Toyocamycin.
Kurihara, Y., Egawa, K., Kunimoto, S., TAKEUCHI, T., & Nose, K. (2002) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.25.1272 · Cited by 15
Epigenetic Changes Accompanying Human Mammary Epithelial Cell Immortalization
Yaswen, P., & Stampfer, M. R. (2001) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/a:1011364925259 · Cited by 15
“Studies indicate that the p16 gene is intact, but that the locus is specifically methylated in post-selection HMEC (4, 12).”
BackgroundSelf-citationHerbert, B., Pearce, V., Hynan, L. S., LaRue, D. M., Wright, W. E., Kopelovich, L., & Shay, J. W. (2003) · PubMed · Cited by 14
p15INK4B is an alternative marker of senescent tumor cells in colorectal cancer
Park, S. S., Lee, Y., Park, S. H., Lim, S. B., Choi, Y. W., Shin, J. S., Kim, Y. H., Kim, J., & Park, T. J. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e13170 · Cited by 14
Molecular Mechanisms of Cellular Senescence
Becker, T. M., & Haferkamp, S. (2013) · InTech eBooks · doi:10.5772/54120 · Cited by 17
“With regard to senescence, it is long known that p16INK4a levels accumulate and cause growth arrest and senescence when cells approach their replicative life span [16-23].”
Background
Metadata
- Authors
- Brenner, A. J., Stampfer, M. R., & Aldaz, C. M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Lawrence Berkeley National Laboratory (US)
- Venue
- Oncogene
- Published
- 1998-07-16
- Volume
- 17
- Issue
- 2
- Pages
- 199-205
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1979165906
- Cited by
- 272
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 10 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 8 · 2014: 4 · 2013: 12 · 2012: 9
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-24844)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p16INK4a, replicative senescence, mammary epithelial cells, senescence-associated β-galactosidase, DNA methylation, decitabine, p21, Rb pathway, tumor suppressor inactivation, cell immortalization, growth arrest, breast cancer
- MeSH terms
- beta-Galactosidase, Breast, Epithelial Cells, Female, Humans, Promoter Regions, Genetic, Cyclins, Cellular Senescence, DNA Methylation, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21
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