Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers
Abstract
Cytogenetic abnormalities of chromosome 9p21 are characteristic of malignant melanomas, gliomas, lung cancers and leukaemias. From a panel of 46 human malignant cell lines, we localized by positional cloning the most frequently deleted region on 9p21. Sequence analysis of the isolated fragment reveals two open reading frames identical to the recently described complementary DNA for the inhibitor of cyclin-dependent kinase 4 (CDK4). Polymerase chain reaction and Southern blot analysis confirmed the frequent deletion or rearrangement of the CDK4-inhibitor gene in melanomas, gliomas, lung cancers and leukaemias, and the absence of detectable gene transcripts. One carcinoma had a deletion entirely within the CDK4-inhibitor gene. The CDK4-inhibitor gene from a patient with dysplastic nevus syndrome had a germ-line nonsense mutation. The CDK4 inhibitor is thought to be a physiological suppressor of proliferation. Cells unable to produce the inhibitor may be prone to neoplastic transformation.
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Culture adaptation is a strong selector against an intact senescence response, especially if multi-passage cell lines and not primary cells are used.
“Of note, culture adaptation is a strong selector against an intact senescence response, especially if multi- passage cell lines and not primary cells are used 188 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [188]
Cites
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
Serrano, M., Hannon, G. J., & Beach, D. (1993) · Nature · doi:10.1038/366704a0 · Cited by 3,650 · see citing works
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Cited by
Sorted by citations
Sherr, C. J. (1996) · Science · doi:10.1126/science.274.5293.1672 · Cited by 5,379 · see citing works
The retinoblastoma protein and cell cycle control
Weinberg, R. A. (1995) · Cell · doi:10.1016/0092-8674(95)90385-2 · Cited by 4,862 · see citing works
pl5INK4B is a potentia| effector of TGF-β-induced cell cycle arrest
Hannon, G. J., & Beach, D. (1994) · Nature · doi:10.1038/371257a0 · Cited by 1,950 · see citing works
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585 · see citing works
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566 · see citing works
Ouelle, D. E., Zindy, F., Ashmun, R. A., & Sherr, C. J. (1995) · Cell · doi:10.1016/0092-8674(95)90214-7 · Cited by 1,485 · see citing works
Toxic effects of ultraviolet radiation on the skin
Matsumura, Y., & Ananthaswamy, H. N. (2004) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2003.08.019 · Cited by 1,270 · see citing works
Di Leonardo, A., Linke, S. P., Clarkin, K., & Wahl, G. M. (1994) · Genes & Development · doi:10.1101/gad.8.21.2540 · Cited by 1,215 · see citing works
Characterizing the cancer genome in lung adenocarcinoma
Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., et al. (2007) · Nature · doi:10.1038/nature06358 · Cited by 1,105 · see citing works
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., & Barrett, J. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13742 · Cited by 1,008 · see citing works
Sherr, C. J. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89005-2 · Cited by 980 · see citing works
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16
Lukas, J., Parry, D., Aagaard, L., Mann, D. J., Bartkova, J., Strauss, M., Peters, G., & Bartek, J. (1995) · Nature · doi:10.1038/375503a0 · Cited by 899 · see citing works
Else, T., Kim, A. C., Sabolch, A., Raymond, V. M., Kandathil, A., Caoili, E. M., Jolly, S., Miller, B. S., Giordano, T. J., & Hammer, G. D. (2014) · Endocrine Reviews · doi:10.1210/er.2013-1029 · Cited by 892 · see citing works
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer
(1996) · Advances in cancer research · doi:10.1016/s0065-230x(08)60352-8 · Cited by 752 · see citing works
Hara, E., Smith, R., Parry, D., Tahara, H., Stone, S., & Peters, G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.859 · Cited by 733 · see citing works
Russo, A. A., Tong, L., Lee, J.-O., Jeffrey, P. D., & Pavletich, N. P. (1998) · Nature · doi:10.1038/26155 · Cited by 524 · see citing works
Melanoma: from mutations to medicine
Tsao, H., Chin, L., Garraway, L. A., & Fisher, D. E. (2012) · Genes & Development · doi:10.1101/gad.191999.112 · Cited by 496 · see citing works
Growth suppression by p16ink4 requires functional retinoblastoma protein
Medema, R. H., Herrera, R. E., Lam, F., & Weinberg, R. A. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6289 · Cited by 433 · see citing works
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M., Masback, A., Westerdahl, J., Olsson, H., & Ingvar, C. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.15.1260 · Cited by 345 · see citing works
Cyclin-Binding Motifs Are Essential for the Function of p21 <i> <sup>CIP1</sup> </i>
Chen, J., Saha, P., Kornbluth, S., Dynlacht, B. D., & Dutta, A. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4673 · Cited by 320 · see citing works
A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis
Kollmann, K., Heller, G., Schneckenleithner, C., Warsch, W., Scheicher, R., Ott, R. G., Schäfer, M., Fajmann, S., Schlederer, M., Schiefer, A.-I., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.07.012 · Cited by 313 · see citing works
Coordinated regulation of life and death by RB
Chau, B. N., & Wang, J. Y. J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc993 · Cited by 292 · see citing works
Witkiewicz, A. K., Knudsen, K. E., Dicker, A. P., & Knudsen, E. S. (2011) · Cell Cycle · doi:10.4161/cc.10.15.16776 · Cited by 286 · see citing works
Mutations associated with familial melanoma impair p16INK4 function
Ranade, K., Hussussian, C. J., Sikorski, R. S., Varmus, H. E., Goldstein, A. M., Tucker, M. A., Serrano, M., Hannon, G. J., Beach, D., & Dracopoli, N. C. (1995) · Nature Genetics · doi:10.1038/ng0595-114 · Cited by 280 · see citing works
Wu, H., Wade, M., Krall, L., Grisham, J., Xiong, Y., & Van Dyke, T. (1996) · Genes & Development · doi:10.1101/gad.10.3.245 · Cited by 234 · see citing works
Tigan, A.-S., Bellutti, F., Kollmann, K., Tebb, G., & Sexl, V (2016) · Oncogene · doi:10.1038/onc.2015.407 · Cited by 204 · see citing works
Epigenetic regulation of the<i>INK4b-ARF-INK4a</i>locus: In sickness and in health
Popov, N., & Gil, J. (2010) · Epigenetics · doi:10.4161/epi.5.8.12996 · Cited by 202 · see citing works
Rane, S. G., Cosenza, S. C., Mettus, R. V., & Reddy, E. P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.644-656.2002 · Cited by 167 · see citing works
Mettus, R. V., & Rane, S. G. (2003) · Oncogene · doi:10.1038/sj.onc.1206888 · Cited by 97 · see citing works
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 · see citing works
MicroRNA controls of cellular senescence
Suh, N. (2018) · BMB Reports · doi:10.5483/bmbrep.2018.51.10.209 · Cited by 78 · see citing works
Hiroyasu, M., Ozeki, M., Kohda, H., Echizenya, M., Tanaka, T., Hiai, H., & Toyokuni, S. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64860-2 · Cited by 61 · see citing works
Wang, T.-J., Huang, M.-S., Hong, C.-Y., Tse, V., Silverberg, G. D., & Hsiao, M. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5565 · Cited by 44 · see citing works
- Authors
- Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K., & Carson, D. A.
- Affiliations
- University of California System (US)
- Venue
- Nature
- Published
- 1994-04
- Volume
- 368
- Issue
- 6473
- Pages
- 753-756
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1997073961
- Cited by
- 1,742
- References
- 1
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 19 · 2023: 21 · 2022: 29 · 2021: 20 · 2020: 21 · 2019: 28 · 2018: 21 · 2017: 25 · 2016: 28 · 2015: 29 · 2014: 27 · 2013: 60 · 2012: 39
- FWCI
- 77.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CDKN2A, p16INK4, chromosome 9p21, tumor suppressor loss, melanoma, glioma, lung cancer, leukemia, dysplastic nevus syndrome, nonsense mutation, germline mutations, oncogenic transformation, positional cloning
- MeSH terms
- Base Sequence, Carrier Proteins, Chromosome Mapping, Chromosomes, Human, Pair 9, DNA, Humans, Molecular Sequence Data, Neoplasms, Proto-Oncogene Proteins, Purine-Nucleoside Phosphorylase, Tumor Cells, Cultured, Genes, Tumor Suppressor, Cyclins, Gene Deletion, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4
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