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Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.
Abstract
The cell-cycle inhibitor p21 is upregulated during senescence and upon induction of senescence-like arrest by oncogenic Ras. We have used primary fibroblasts derived from p21-null mice to evaluate the role of p21 in these processes. We find that primary p21-/- cells enter senescence and have a lifespan similar to wild-type cells. Upon immortalization, most wild-type and p21-/- cultures acquire alterations in either p53 or p16INK4a, further indicating that p21-deficiency is not sufficient by itself to allow immortalization. Primary p21-/- cells, like wild-type cells, respond to oncogenic Ras by accumulating p53 and p16INK4a, and by decreasing their proliferation rate. In agreement with this, p21-/- cells are refractory to neoplasic transformation by oncogenic Ras when compared to p53-/- cells. We conclude that, in murine fibroblasts, p21 is not essential neither for senescence nor for preventing neoplasic transformation by oncogenic Ras.
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“Increased expression of p21 also plays a role in induction of senescence, particularly during its initiation.26”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [26]
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BackgroundRole of p14ARF in Replicative and Induced Senescence of Human Fibroblasts
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“Second, ectopic expression of Arf arrested p21 / MEFs (25), while it could not arrest p21 / human fibroblasts (this communication).”
BackgroundInfluentialWide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208
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Tbx2 Directly Represses the Expression of the p21WAF1 Cyclin-Dependent Kinase Inhibitor
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Uncoupling between Phenotypic Senescence and Cell Cycle Arrest in Aging p21-Deficient Fibroblasts
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“Nevertheless, as described previously (45), late-passage p21 MEFs have a senescent morphology (but not SA–b-Gal) when their population expansion ceases (or reaches a plateau in the case of cultures that eventually immortalize) owing to crisislike events.”
BackgroundResultBrummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110492200 · Cited by 154
Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence
Larsson, L. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.10.005 · Cited by 152
Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L. T., & Serrano, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0200 · Cited by 140
“genotype were obtained as previously described (35) and grown in the”
MethodZou, X., Ray, D., Aziyu, A., Christov, K. T., Boiko, A. D., Gudkov, A. V., & Kiyokawa, H. (2002) · Genes & Development · doi:10.1101/gad.1033002 · Cited by 146
“However, p21Cip1/Waf1-null MEFs with intact Cdk4 senesce normally (Pantoja and Serrano 1999), andMEFs from p21Cip1/Waf1, Cdk4-double null mice poorly undergo transformation upon expression of H-RasVal12 and DNp53 (X. Zou and H. Kiyokawa, unpubl.).”
BackgroundShvarts, A., Brummelkamp, T. R., Scheeren, F., Koh, E., Daley, G. Q., Spits, H., & Bernards, R. (2002) · Genes & Development · doi:10.1101/gad.929302 · Cited by 145
“…genetic ablation of p16INK4A alone or p21cip1 in mouse embryonic fibroblasts (MEFs) does not render cells resistant to the induction of senescence (Pantoja and Serrano 1999; Krimpenfort et al. 2001), even though enforced expression of p16INK4A or p21cip1 (McConnell et al. 1998; Dai and Enders…”
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“However, data obtained in studies with human and mouse fibroblasts showed in part divergent results with respect to the role of p21 during immortalization (7, 37).”
ResultIncreased 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
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The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescencePreprint
Aksoy, O., Chicas, A., Zeng, T., Zhao, Z., McCurrach, M. E., Wang, X., & Lowe, S. W. (2012) · Genes & Development · doi:10.1101/gad.196238.112 · Cited by 130
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BackgroundMolecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging
Zhang, H. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20919 · Cited by 136
“Interestingly, mouse embryo fibroblasts (MEFs) carrying a null mutation in p21 undergo senescence normally (Pantoja and Serrano, 1999), indicating that p21 is not a critical link downstream of p53 during senescence in rodent cells.”
BackgroundDoes p53 affect organismal aging?
Donehower, L. A. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10104 · Cited by 155
“In other instances, a p53-dependent induction of senescence could be generated in the absence of p21 (Pantoja and Serrano, 1999; Groth et al., 2000; Wei et al., 2001).”
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Rowland, B. D., Denissov, S. G., Douma, S., Stunnenberg, H. G., Bernards, R., & Peeper, D. S. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00085-5 · Cited by 120
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p53 downstream target genes and tumor suppression: a classical view in evolution
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A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence
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“Lymphomas were classified according to the criteria of Pattengale and Firth (1986).”
MethodLoss of p53 Induces Tumorigenesis in p21-Deficient Mesenchymal Stem Cells
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“Moreover, spontaneous immortalization of murine fibroblasts is frequently associated with a mutation of p53 [41], and wild-type and p21 MEF cultures acquire alterations in p53 [42].”
Backgroundp53-Dependent and -Independent Functions of the Arf Tumor SuppressorPreprint
Sherr, C. J., Bertwistle, D., den Besten, W., KUO, M.-L., SUGIMOTO, M., Tago, K., Williams, R. T., Zindy, F., & Roussel, M. F. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.004 · Cited by 106
“Although these manipulations ultimately prove toxic, inhibition of Arf-induced sumoylation of Mdm2 had no immediate effect on p53 stabilization or on the induction of canonical p53-responsive genes, such as Cip1 or Mdm2 itself (Tago et al. 2005).”
BackgroundInfluentialMultiple E2F-Induced MicroRNAs Prevent Replicative Stress in Response to Mitogenic Signaling
Bueno, M. J., de Cedrón, M. G., Laresgoiti, U., Fernández‐Piqueras, J., Zubiaga, A. M., & Malumbres, M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01372-09 · Cited by 103
“However, downregulation or p21 does not promote cell cycle progression in primary MEFs (56), and indeed, it may be important to support cyclin D-CDK4 activity in these primary cells (64).”
BackgroundArf induces p53-dependent and -independent antiproliferative genes.
Kuo, M.-L., Duncavage, E. J., Mathew, R., den Besten, W., Pei, D., Naeve, D., Yamamoto, T. S., Cheng, C., Sherr, C. J., & Roussel, M. F. (2003) · PubMed · Cited by 99
Transcriptional regulation of cellular senescence
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“Interestingly, in mouse fibroblasts, the loss of p21 does not recapitulate p53 loss, and these cells still undergo cellular senescence (Pantoja and Serrano, 1999).”
Integration of positive and negative growth signals during ras pathway activation in vivo
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Groth, A., Weber, J. D., Willumsen, B. M., Sherr, C. J., & Roussel, M. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003417200 · Cited by 92
Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control
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“However, since mutations in the p21Waf1/Cip1/Sdi1 gene are rarely observed in human cancers and mice lacking p21Waf1/Cip1/ Sdi1 gene do not exhibit any predisposition to spontaneous tumor formation [37-40], it remains unclear whether p21Cip1/Waf1/Sdi1 indeed plays a key role in tumor suppression in vivo.”
BackgroundLoss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model
Adnane, J., Jackson, R. J., Nicosia, S. V., Cantor, A. B., Pledger, W. J., & Sebti, S. M. (2000) · Oncogene · doi:10.1038/sj.onc.1203956 · Cited by 91
“This is in agreement with a study that showed that p21-null primary murine ®broblasts were resistant to transfor- Oncogene mation by oncogenic ras and that additional changes were necessary to achieve a fully transformed phenotype (Pantoja and Serrano, 1999).”
ResultCudré-Mauroux, C., Occhiodoro, T., König, S., Salmon, P., Bernheim, L., & Trono, D. (2003) · Human Gene Therapy · doi:10.1089/104303403322495034 · Cited by 86
“In the contrary, MEFs from p21 null mice senesce normally (Pantoja and Serrano, 1999).”
Replicative senescence revisited.
Marcotte, R., & Wang, E. (2002) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/57.7.b257 · Cited by 86
“Pantoja C, Serrano M. Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.”
BackgroundInfluentialCastillo, S. D., Matheu, A., Mariani, N., Carretero, J., López‐Ríos, F., Lovell-Badge, R. H., & Sánchez‐Céspedes, M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-3506 · Cited by 85
“Mouse embryo fibroblasts (MEF) were isolated and cultured as previously described (26) from Sox4þ/þ, Sox4þ/ , and Sox4 / E13.”
MethodTumor suppression by p53: making cells senescent.
Qian, Y., & Chen, X. (2010) · PubMed · doi:10.14670/hh-25.515 · Cited by 85
“In agreement with this, MEFs derived from p21null mice eventually enter senescence (Pantoja and Serrano, 1999).”
Exploiting tumor cell senescence in anticancer therapy
Lee, M., & Lee, J. (2014) · BMB Reports · doi:10.5483/bmbrep.2014.47.2.005 · Cited by 85
“stream effector of p53 during senescence in mouse cells (39, 40).”
BackgroundGrowth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation
Fiorentino, F. P., Tokgün, P. E., Solé‐Sánchez, S., Giampaolo, S., Tokgün, O., Jauset, T., Kohno, T., Perucho, M., Soucek, L., & Yokota, J. (2016) · Oncotarget · doi:10.18632/oncotarget.8826 · Cited by 80
“Cell growth assays were performed with a modification of serial cultivation method [49].”
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
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Therapeutic targeting of replicative immortality
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“However, in MEFs, the absence of 21 does not prevent senescence [106,107].”
BackgroundYPEL3, a p53-Regulated Gene that Induces Cellular Senescence
Kelley, K. D., Miller, K. R., Todd, A., Kelley, A. R., Tuttle, R., & Berberich, S. J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3219 · Cited by 73
“Although it is accepted that cyclindependent kinase inhibitor and p53 target gene p21 is induced as cells undergo senescence, in some cell systems, the loss of p21 leads to senescence bypass (7); yet in other cell systems, p21-null cells can still undergo a ras-mediated senescence (8).”
BackgroundYang, X., He, Z., Xin, B., & Cao, L. (2000) · Oncogene · doi:10.1038/sj.onc.1203515 · Cited by 71
“Mutation in p16 or p53, but not p21, abolishes oncogene ras induced premature senescence of MEF cells (Serrano et al., 1997; Pantoja and Serrano, 1999).”
BackgroundMarkers of cellular senescence.
Carnero, A. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_4 · Cited by 68
Geserick, C., Tejera, Á. M., González‐Suárez, E., Klatt, P., & Blasco, M. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209465 · Cited by 71
“Serial 3T3 cultivation and calculation of population doublings, as well as colony-formation assays were performed as described (Pantoja and Serrano, 1999).”
MethodLoss of CCAAT/enhancer binding protein δ promotes chromosomal instability
Huang, A., Montagna, C., Sharan, S., Ni, Y., Ried, T., & Sterneck, E. (2004) · Oncogene · doi:10.1038/sj.onc.1207285 · Cited by 70
“However, the MEF display G1 checkpoint defects, and the mutation indeed contributes in vivo to tumorigenesis when induced by, for example, oncogenic Ras or chemical carcinogenesis (Deng et al., 1995; Pantoja and Serrano, 1999; Jackson et al., 2002).”
BackgroundPuimedon, M. S., Sahún, I., Velot, É., Dubus, P. R., Borralleras, C., Rodrigues, A. J., Valero, M. C., Valverde, O., Sousa, N., Hérault, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu368 · Cited by 71
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
Jirawatnotai, S., Moons, D. S., Stocco, C. O., Franks, R. R., Hales, D. B., Gibori, G., & Kiyokawa, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301206200 · Cited by 64
Rimessi, A., Marchi, S., Patergnani, S., & Pinton, P. (2013) · Oncogene · doi:10.1038/onc.2013.192 · Cited by 68
ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells
Wang, Y., Godin-Heymann, N., WANG, X.-D., Bergamaschi, D., Llanos, S., & Lü, X. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.3 · Cited by 60
p53-dependent senescence delays Eμ-myc-induced B-cell lymphomagenesis
Post, S. M., Quintás‐Cardama, A., Terzian, T., Smith, C., Eischen, C. M., & Lozano, G. (2009) · Oncogene · doi:10.1038/onc.2009.423 · Cited by 58
“Transfection of oncogenic Ras induces senescence in MEFs carrying wild-type p53, which results in low transformation potential (Serrano et al., 1997; Pantoja and Serrano, 1999).”
BackgroundLimited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression
Efeyan, A., Murga, M., Martínez-Pastor, B., Ortega-Molina, A., Soria, R., Collado, M., Fernández-Capetillo, Ó., & Serrano, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005475 · Cited by 63
“5 embryos as previously described [52] and grown in Dulbecco’s Minimum Essential Media (DMEM, Invitrogen, Grand Island, NY, USA) supplemented with 10% FBS (Hyclone, Logan, UT).”
MethodThrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors
Baek, K., Bhang, D., Zaslavsky, A., Wang, L.-C., Vachani, A., Kim, C. F., Albelda, S. Μ., Evan, G. I., & Ryeom, S. W. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67465 · Cited by 57
“Consistent with studies showing that p21 cip1 induction, while necessary, is not sufficient for oncogene-induced senescence (28, 35, 36), p21 cip1 was induced after oncogenic Ras activation — but at a substantially lower level in the absence of TSP-1 — in lung fibroblasts, lung epithelial cells,…”
Cell-specific pattern of berberine pleiotropic effects on different human cell lines
Agnarelli, A., Natali, M., Garcia‐Gil, M., Pesi, R., Tozzi, M. G., Ippolito, C., Bernardini, N., Vignali, R., Batistoni, R., Bianucci, A. M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-28952-3 · Cited by 57
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence
Kalinin, A., Zubkova, E., & Menshikov, M. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417423 · Cited by 62
“For example, cellular senescence is possible in primary fibroblasts from p21 knockout mice, and resistance to senescence is observed in certain mouse hepatic tumor cells despite p21CIP1/WAF1 expression [30].”
BackgroundGomez-Sanchez, J. A., Gomis-Coloma, C., Morenilla‐Palao, C., Peiró, G., Serra, E., Serrano, M., & Cabedo, H. (2013) · Brain · doi:10.1093/brain/awt130 · Cited by 56
“However, it has been shown that p21cip / fibroblasts can enter the senescence programme (Pantoja and Serrano, 1999).”
BackgroundH-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism
Delgado, M. D., Vaque, J. P., Arozarena, I., Lopez-Ilasaca, M. A., Martínez, C., Crespo, P., & León, J. (2000) · Oncogene · doi:10.1038/sj.onc.1203384 · Cited by 55
“…mechanisms could operate subsequently to p21WAF1 mediated growth arrest, as autophagic degeneration (Chi et al., 1999) or cellular senescence (Serrano et al., 1997; Fang et al., 1999) although in murine ®broblasts p21WAF1 is not essential for Ras-mediated senescence (Pantoja and Serrano, 1999).”
BackgroundCellular senescence or stemness: hypoxia flips the coin
Otero-Albiol, D., & Carnero, A. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02035-0 · Cited by 56
Paramio, J. M., Segrelles, C., Ruiz, S., Martín‐Caballero, J., Page, A., Martínez, J. L., Serrano, M., & Jorcano, J. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105650200 · Cited by 51
Bcl-2 protects against oxidative stress while inducing premature senescence
López‐Díazguerrero, N. E., López-Araiza, H., Conde-Pérezprina, J. C., Bucio, L., Cárdenas‐Aguayo, M. D. C., Ventura, J. L., Covarrubias, L., Gutiérrez‐Ruíz, M. C., Zentella‐Dehesa, A., & Königsberg, M. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.11.002 · Cited by 50
Lin, S., Yang, J., ELKAHLOUN, A. G., Bandyopadhyay, A. M., Wang, L., Cornell, J. E., Yeh, I., Agyin, J. K., Tomlinson, G. E., & Sun, L. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0849 · Cited by 52
“Published studies have shown that deletion of p21 gene is not sufficient for mouse fibroblasts to bypass Ras-induced senescence (Pantoja and Serrano, 1999) but is sufficient for the transformation of mouse keratinocytes by Ras (Missero et al.”
BackgroundMelanomagenesis: Overcoming the barrier of melanocyte senescence
Ha, L., Merlino, G. T., & Sviderskaya, E. V. (2008) · Cell Cycle · doi:10.4161/cc.7.13.6230 · Cited by 50
Animal and human models to understand ageing
Lees, H., Walters, H., & Cox, L. S. (2016) · Maturitas · doi:10.1016/j.maturitas.2016.06.008 · Cited by 50
“Induction of senescence in mice relies heavily on the p16 cyclin kinase inhibitor CDKN2A, while p21 CDKN1A may be more important in some cell types in humans [73].”
BackgroundThe Retinoblastoma Gene Family in Cell Cycle Regulation and Suppression of Tumorigenesis
Dannenberg, J.-H., & te Riele, H. P. J. (2006) · Results and Problems in Cell Differentiation · doi:10.1007/400_002 · Cited by 47
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
“Although the importance of p21 on senescence has been well reported[6-9], the question of whether p21 is essential for the establishment of senescence still needs to be answered definitely, at least in murine cells[10-12].”
BackgroundOncogene-induced senescence: An essential role for Runx
Terry, A., Cameron, E. R., Neil, J. C., & Kilbey, A. (2008) · Cell Cycle · doi:10.4161/cc.6368 · Cited by 51
Cellular Senescence as a Target in Cancer Control
Vergel, M., Marín, J., Estévez, P., & Carnero, A. (2010) · Journal of Aging Research · doi:10.4061/2011/725365 · Cited by 45
“Eukaryotic cells cannot replicate the very ends of their chromosomes, the telomeres, resulting in shortening their lengths with every cell division until they reach a critical threshold, at which point cells stop replicating [11].”
Backgroundp21 as a Transcriptional Co-Repressor of S-Phase and Mitotic Control Genes
Ferrándiz, N., Caraballo, J. M., García-Gutiérrez, L., Devgan, V., Rodríguez‐Paredes, M., Lafita‐Navarro, M. C., Bretones, G., Quintanilla, A., Muñoz-Alonso, M. J., Blanco, R. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037759 · Cited by 48
“inducer of senescence [15,16,17] or differentiation (reviewed in [18]).”
BackgroundSecretome of Human Fetal Mesenchymal Stem Cell Ameliorates Replicative Senescence
Wang, B., Lee, W., Huang, B., Zhang, J., Wu, T., Jiang, X., Wang, C. C., & Li, G. (2016) · Stem Cells and Development · doi:10.1089/scd.2016.0079 · Cited by 48
Metadata
- Authors
- Pantoja, C., & Serrano, M.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Venue
- Oncogene
- Published
- 1999-09-02
- Volume
- 18
- Issue
- 35
- Pages
- 4974-4982
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2081779271
- Cited by
- 201
- References
- 78
- Citations by year
- 2025: 3 · 2023: 6 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 6
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- 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
- p21, cellular senescence, oncogenic Ras, oncogenic transformation, p53, p16INK4a, cell cycle inhibitors, fibroblasts, cell immortalization
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, Cells, Cultured, Doxorubicin, Fibroblasts, Serial Passage, Transduction, Genetic, Oncogene Protein p21(ras), Gene Expression, Tumor Suppressor Protein p53, Cyclins, 3T3 Cells, Cellular Senescence, Gene Deletion, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Mice
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