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The meaning of p16ink4aexpression in tumors: Functional significance, clinical associations and future developments
Open accessAbstract
The CDKN2A gene is a tumor suppressor that encodes the CDK4/6 inhibitor p16(ink4a). Loss of this tumor suppressor contributes to the bypass of critical senescent signals and is associated with progression to malignant disease. However, the high-level expression of p16(ink4a) in tumors is associated with aggressive subtypes of disease, and in certain clinical settings elevated p16(ink4a) expression is an important determinant for disease prognosis and therapeutic response. These seemingly contradictory facets of p16(ink4a) expression have lead to confusion related to the meaning of this tumor suppression in tumor pathobiology. As reviewed here, the alternative expression of p16(ink4a) represents an ideal marker for considering RB-pathway function, tumor heterogeneity, and novel means for directing therapy.
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“In agreement with p16's role as a guardian of senescence, mutations, silencing or loss of CDKN2A, the gene encoding p16, facilitate senescence bypass and it is frequently associated with carcinogenesis (reviewed in.51,52”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [52]
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Cites
Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer
Ang, K. K., Harris, J., Wheeler, R. H., Weber, R. S., Rosenthal, D. I., Nguyen‐Tan, P. F., Westra, W. H., Chung, C. H., Jordan, R. C., Lu, C. S., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0912217 · Cited by 6,573
CDK inhibitors: positive and negative regulators of G1-phase progression
Sherr, C. J., & Roberts, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.12.1501 · Cited by 6,115
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
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 · cited 1×
“The p16 protein was identified as a low molecular weight protein bound to cyclin dependent kinase 4 and 6 (CDK4 and CDK6).(1,2) This biochemical characterization was largely facilitated by the finding that in tumor cells transformed by SV40 the sole form of CDK4 that was detectable was in complex with p16.”
BackgroundThe human papilloma virus-16 E7-oncoprotein is able to bind to the retinoblastoma gene product
Dyson, N., Howley, P. M., Münger, K., & Harlow, E. (1989) · Science · doi:10.1126/science.2537532 · Cited by 3,017
Fakhry, C., Westra, W. H., Li, S., Cmelak, A. J., Ridge, J. A., Pinto, H. A., Forastiere, A. A., & Gillison, M. L. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn011 · Cited by 2,777
A cell cycle regulator potentially involved in genesis of many tumor types
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., Johnson, B. E., & Skolnick, M. H. (1994) · Science · doi:10.1126/science.8153634 · Cited by 2,751 · cited 1×
“Initially, it was observed that the gene encoding CDKN2A was mutated or silenced in a wide spectrum of tumor types and cell lines.(20,21) Particularly, loss or epigenetic silencing of CDKN2A is very common in cell lines, suggesting that the process of cell culture selects against the expression of p16.”
BackgroundBRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization
Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.22.3499 · Cited by 2,130
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986
Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers
Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K., & Carson, D. A. (1994) · Nature · doi:10.1038/368753a0 · Cited by 1,742
Senescence in premalignant tumours
Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguría, A., Zaballos, A., Flores, J. M., Barbacid, M., et al. (2005) · Nature · doi:10.1038/436642a · Cited by 1,482
(1993) · Genes & Development · doi:10.1101/gad.7.3.331 · Cited by 1,264
Fry, D. W., Harvey, P. J., Keller, P. R., Elliott, W. L., Meade, M., Trachet, E., Albassam, M., Zheng, X., Leopold, W. R., Pryer, N. K., et al. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.1427.3.11 · Cited by 1,236
Münger, K., Werness, B. A., Dyson, N. J., Phelps, W. C., Harlow, E. E., & Howley, P. M. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08594.x · Cited by 1,204
A p16 INK4a -Insensitive CDK4 Mutant Targeted by Cytolytic T Lymphocytes in a Human Melanoma
Wölfel, T., Hauer, M., Schneider, J., Serrano, M., Wölfel, C., Klehmann, E., Plaen, E. D., Hankeln, T., Büschenfelde, K. M. Z., & Beach, D. (1995) · Science · doi:10.1126/science.7652577 · Cited by 1,171
Cellular mechanisms of tumour suppression by the retinoblastoma gene
Burkhart, D. L., & Sage, J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2399 · Cited by 974
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
Matsushime, H., Ewen, M. E., Strom, D. K., Kato, J.-Y., Hanks, S. K., Roussel, M. F., & Sherr, C. J. (1992) · Cell · doi:10.1016/0092-8674(92)90360-o · Cited by 897
Progression model for pancreatic cancer.
Hruban, R. H., Goggins, M., Parsons, J., & Kern, S. E. (2000) · PubMed · Cited by 872
Role of the p16 tumor suppressor gene in cancer.
Liggett, W. H., & Sidransky, D. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.3.1197 · Cited by 746
Rischin, D., Young, R. J., Fisher, R., Fox, S. B., Le, Q., Peters, L. J., Solomon, B., Choi, J., O’Sullivan, B., Kenny, L., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.29.2904 · Cited by 735
Oncogenic Braf Induces Melanocyte Senescence and Melanoma in Mice
Dhomen, N. S., Reis-Filho, J. S., Dias, S. D. R., Hayward, R., Savage, K., Delmas, V., Larue, L., Pritchard, C. A., & Marais, R. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.02.022 · Cited by 626
p16 INK4A is a robust in vivo biomarker of cellular aging in human skin
Ressler, S., Bartkova, J., Niederegger, H., Bartek, J., Scharffetter‐Kochanek, K., Jansen‐Dürr, P., & Wlaschek, M. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00231.x · Cited by 557
Russo, A. A., Tong, L., Lee, J.-O., Jeffrey, P. D., & Pavletich, N. P. (1998) · Nature · doi:10.1038/26155 · Cited by 524
Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.Preprint
Xiong, Y., Zhang, H., & Beach, D. (1993) · Genes & Development · doi:10.1101/gad.7.8.1572 · Cited by 507
Cheng, M., Sexl, V., Sherr, C. J., & Roussel, M. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.1091 · Cited by 496
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
Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure
Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A., & Knudsen, E. S. (2010) · Oncogene · doi:10.1038/onc.2010.154 · Cited by 393
Self-citationTailoring to RB: tumour suppressor status and therapeutic response
Knudsen, E. S., & Knudsen, K. E. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2401 · Cited by 354
Self-citationRetinoblastoma protein partners
(2001) · Advances in Cancer Research · doi:10.1016/s0065-230x(01)82001-7 · Cited by 349
Sharma, A. M., Yeow, W.-S., Ertel, A., Coleman, I. M., Clegg, N. J., Thangavel, C., Morrissey, C. M., Zhang, X., Comstock, C. E. S., Witkiewicz, A. K., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci44239 · Cited by 332
Self-citationMichaud, K., Solomon, D. A., Oermann, E. K., Kim, J.-S., Zhong, W.-Z., Prados, M. D., Ozawa, T., James, C. D., & Waldman, T. A. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4559 · Cited by 330
Otterson, G. A. (1995) · Lung Cancer · doi:10.1016/0169-5002(95)98734-r · Cited by 314
Knudsen, E. S., & Wang, J. Y. J. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.10.5771 · Cited by 285
Self-citationMutations 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
Herschkowitz, J. I., He, X., Fan, C., & Perou, C. M. (2008) · Breast Cancer Research · doi:10.1186/bcr2142 · Cited by 261
Suppressing Cancer: The Importance of Being Senescent
Campisi, J. (2005) · Science · doi:10.1126/science.1116801 · Cited by 255
Management of Small Cell Lung Cancer
Simon, G. R., & Turrisi, A. T. (2007) · CHEST Journal · doi:10.1378/chest.07-1385 · Cited by 225
Gauthier, M. L., Berman, H. K., Miller, C., Kozakeiwicz, K., Chew, K., Moore, D., Rabban, J., Chen, Y. Y., Kerlikowske, K., & Tlsty, T. D. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.10.017 · Cited by 214
Kong, C. S., Narasimhan, B., Cao, H., Kwok, S., Erickson, J. P., Koong, A. C., Pourmand, N., & Le, Q. (2009) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2009.02.015 · Cited by 213
Targeting the RB-pathway in Cancer Therapy
Knudsen, E. S., & Wang, J. Y. J. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0787 · Cited by 210
Self-citationInhibition of DNA synthesis by RB: effects on G1/S transition and S-phase progressionPreprint
Knudsen, E. S., Buckmaster, C., Chen, T.-T., Feramisco, J. R., & Wang, J. Y. J. (1998) · Genes & Development · doi:10.1101/gad.12.15.2278 · Cited by 209
Self-citationThe retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer
Bosco, E. E., Wang, Y., Xu, H., Zilfou, J. T., Knudsen, K. E., Aronow, B. J., Lowe, S. W., & Knudsen, E. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28803 · Cited by 192
Self-citationRole of the CDKN2A Locus in Patients With Multiple Primary Melanomas
Puig, S., Malvehy, J., Bádenas, C., Ruiz, A., Jiménez, D., Cuéllar, F., Azón, A., González, U., CASTEL, T., Campoy, A., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.08.034 · Cited by 147
E2F-associated chromatin modifiers and cell cycle control
Blais, A., & Dynlacht, B. D. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.10.003 · Cited by 146
Cell cycle control and cancer.
Sherr, C. J. (2002) · PubMed · Cited by 138
Rivadeneira, D. B., Mayhew, C. N., Thangavel, C., Sotillo, E., Reed, C. A., Graña, X., & Knudsen, E. S. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.01.007 · Cited by 129
Self-citationSubhawong, A. P., Subhawong, T. K., Nassar, H., Kouprina, N., Begum, S., VANG, R. S., Westra, W. H., & Argani, P. (2009) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e31817f9790 · Cited by 111
Retinoblastoma Tumor Suppressor: Where Cancer Meets the Cell Cycle
Knudsen, E. S., & Knudsen, K. E. (2006) · Experimental Biology and Medicine · doi:10.1177/153537020623100713 · Cited by 106
Self-citationCt, L., Capodieci, P., Osman, I., Fazzari, M. J., Ferrara, J., Scher, H. I., & Cordon‐Cardo, C. (1999) · PubMed · Cited by 105
Aagaard, L., Lukas, J., Bártková, J., Kjerulff, A. A., Strauss, M., & Bártek, J. (1995) · International Journal of Cancer · doi:10.1002/ijc.2910610120 · Cited by 102
Tumour vascularity and proliferation: clear evidence of a close relationship
Weidner, N. (1999) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199911)189:3 · Cited by 87
Kelley, M. J., Nakagawa, K., Steinberg, S., Mulshine, J. L., Kamb, A., & Johnson, B. E. (1995) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/87.10.756 · Cited by 80
Henshall, S. M., Quinn, D. I., Lee, C. S., Head, D. R., Golovsky, D., Brenner, P. C., Delprado, W., Stricker, P. D., Grygiel, J. J., & Sutherland, R. L. (2001) · PubMed · Cited by 80
Human Papillomavirus and Head and Neck Cancer
Mendenhall, W. M., & Logan, H. L. (2009) · American Journal of Clinical Oncology · doi:10.1097/coc.0b013e31818b8fee · Cited by 67
Tort, F., Bártková, J., Sehested, M., Orntoft, T. F., Lukas, J., & Bártek, J. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2178 · Cited by 66
Chakravarti, A., DeSilvio, M., Zhang, M., Grignon, D. J., Rosenthal, S. A., Asbell, S. O., Hanks, G. E., Sandler, H. M., Khor, L.-Y., Pollack, A. S., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.4152 · Cited by 52
Loss of Rb overrides the requirement for ERK activity for cell proliferation
D’Abaco, G. M., Hooper, S., Paterson, H., & Marshall, C. J. (2002) · Journal of Cell Science · doi:10.1242/jcs.00161 · Cited by 34
Regulation of CYL /Cyclin D Genes by Colony‐Stimulating Factor 1
Sherr, C. J., Matsushime, H., & Roussel, M. F. (2007) · Novartis Foundation symposium · doi:10.1002/9780470514320.ch13 · Cited by 24
S-phase lengthening induced by p16INK4aoverexpression in malignant cells with wild-type pRb and p53
Chien, W. W., Domenech, C., Catallo, R., Salles, G., & Ffrench, M. (2010) · Cell Cycle · doi:10.4161/cc.9.16.12600 · Cited by 15
Paradoxical down-regulation of p16 mRNA with advancing age in Acute Myeloid Leukemia
de Jonge, H. J. M., Woolthuis, C. M., de Bont, E. S. J. M., & Huls, G. A. (2009) · Aging · doi:10.18632/aging.100096 · Cited by 15
Flagged first, then by citations
Research works printed but not linked: 7
- Sherr CJ, 2000, Harvey Lect, 96, 73
- Sherr CJ, 1992, Ciba Found Symp, 170, 209
- de Jonge HJ, 2009, Aging (Albany, NY Online), 1, 949
- Hruban RH, 2000, Clin Cancer Res, 6, 2969
- Henshall SM, 2001, Clin Cancer Res, 7, 544
- Otterson GA, 1994, Oncogene, 9, 3375
- Lee CT, 1999, Clin Cancer Res, 5, 977
Cited by
Sorted by citations
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Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277
The history and future of targeting cyclin-dependent kinases in cancer therapy
Asghar, U., Witkiewicz, A. K., Turner, N. C., & Knudsen, E. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4504 · Cited by 1,767
Self-citationForging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104
Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448
“Limitations include poor detection of p16INK4a in mice by the currently available antibodies using immunohistochemistry [79], as well as some situations, where p16INK4a levels are increased, in the absence of other signs of cellular senescence [81,83,84].”
BackgroundA multidimensional systems biology analysis of cellular senescence in aging and disease
Avelar, R. A., Ortega, J. G., Tacutu, R., Tyler, E. J., Bennett, D., Binetti, P., Budovsky, A., Chatsirisupachai, K., Johnson, E., Murray, A., et al. (2020) · Genome Biology · doi:10.1186/s13059-020-01990-9 · Cited by 399
Metadata
- Authors
- Witkiewicz, A. K., Knudsen, K. E., Dicker, A. P., & Knudsen, E. S.
- Affiliations
- Thomas Jefferson University (US)
- Corresponding author
- Knudsen, Erik S.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2011-08
- Volume
- 10
- Issue
- 15
- Pages
- 2497-2503
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC3685613
- OpenAlex
- W2019517928
- Cited by
- 286
- References
- 62
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 14 · 2023: 22 · 2022: 29 · 2021: 16 · 2020: 26 · 2019: 26 · 2018: 24 · 2017: 18 · 2016: 13 · 2015: 19 · 2014: 14 · 2013: 19 · 2012: 10
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA099996)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p16INK4a, CDKN2A, tumor suppressor, Rb pathway, cellular senescence, tumor heterogeneity, prognosis, treatment response, tumor progression, CDK4/6 inhibition
- MeSH terms
- Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Retinoblastoma Protein, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin D
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