The DOI matches its Crossref record; 54 of the 56 references it cites were found in a registry or an index.
Tumor suppression by Ink4a-Arf: progress and puzzles.
Abstract
The two products of the Ink4a-Arf locus, p16(Ink4a) and p19(Arf) (p14(ARF) in humans), are potent tumor suppressors that regulate the activities of the retinoblastoma protein and the p53 transcription factor. These proteins form part of a signaling network that is disrupted in most, if not all, cancer cells. The Ink4a-Arf locus responds to stress signals, limiting cell proliferation and modulating oncogene-induced apoptosis. Recent evidence emerging from mouse tumor models distinguishes the activities of p16(Ink4a) and p19(Arf) in regulating tumor onset and identifies differences in their responsiveness to drugs.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [ 12 , 13 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [13]
In the citing paper
“In contrast, p16INK4a is poorly induced in senescent BJ fibroblasts and appears dispensable for senescence in MEFs (Beauséjour et al., submitted; Lowe and Sherr, 2003).”
From Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence (2003) · cites this paper as Lowe and Sherr, 2003
In the citing paper
“In contrast, p16INK4a is poorly induced in senescent BJ fibroblasts and appears dispensable for senescence in MEFs (Beauséjour et al., submitted; Lowe and Sherr, 2003).”
From Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence (2003) · cites this paper as Lowe and Sherr, 2003
In the citing paper
“p16 is induced by a variety of stressful stimuli, including overexpression of oncogenes such as RAS and suboptimal culture conditions (Lowe and Sherr, 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Lowe and Sherr, 2003
In the citing paper
“The p16-Arf locus encodes 2 tumor suppressors, p16 and Arf.10-12”
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 [10]
In the citing paper
“p16 functions as a cyclin-dependent kinase (CDK) 4/6 inhibitor.10”
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 [10]
In the citing paper
“Therefore, activation of p53 by Arf can induce not only senescence but also apoptosis, depending on which gene downstream of p53 is induced after p53 activation.”
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 [10]
In the citing paper
“In contrast, the biological action of Arf relies on the p53 pathway. This is because Arf can directly bind to mouse double minute 2 homolog (MDM2) and cause the accumulation of p53 by segregating MDM2 from p53 and by inhibiting MDM2’s E3 ubiquitin protein ligase activity for p53.10,11,14”
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 [10]
Citations
Cites
Network motifs in the transcriptional regulation network of Escherichia coli
Shen-Orr, S. S., Milo, R., Mangan, S., & Alon, U. S. (2002) · Nature Genetics · doi:10.1038/ng881 · Cited by 2,970
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580
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
Self-citationMayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230
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
Cheng, M., Olivier, P., Diehl, J. A., Fero, M., Roussel, M. F., Roberts, J. M., & Sherr, C. J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1571 · Cited by 1,142
Self-citationTelomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice
Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000) · Nature · doi:10.1038/35020592 · Cited by 1,085
Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARFPreprint
Jacobs, J. J. L., Scheijen, B., Voncken, J. W., Kieboom, K., Berns, A. J. M., & van Lohuizen, M. (1999) · Genes & Development · doi:10.1101/gad.13.20.2678 · Cited by 1,069
A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy
Schmitt, C. A., Fridman, J. S., Yang, M., Lee, S., Baranov, E., Hoffman, R. M., & Lowe, S. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00734-1 · Cited by 1,050
Self-citationThe INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 1,001
Self-citationModelling the molecular circuitry of cancer
Hahn, W. C., & Weinberg, R. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc795 · Cited by 953
p14ARF links the tumour suppressors RB and p53
Bates, S., Phillips, A. C., Clark, P. A., Stott, F., Peters, G., Ludwig, R. L., & Vousden, K. H. (1998) · Nature · doi:10.1038/25867 · Cited by 918
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848
Helper T Cell Differentiation Is Controlled by the Cell Cycle
Bird, J. J., Brown, D. R., Mullen, A. C., Moskowitz, N. H., Mahowald, M. A., Sider, J. R., Gajewski, T. F., Wang, C.-R., & Reiner, S. L. (1998) · Immunity · doi:10.1016/s1074-7613(00)80605-6 · Cited by 834
Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis
Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J., & Cleveland, J. L. (1999) · Genes & Development · doi:10.1101/gad.13.20.2658 · Cited by 819
Self-citationSherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745
Self-citationEpidermal growth factor receptor and Ink4a/Arf
Bachoo, R. M., Maher, E. A., Ligon, K. L., Sharpless, N. E., Chan, S., You, M. J., Tang, Y., DeFrances, J., Stover, E. H., Weissleder, R., et al. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00046-6 · Cited by 659
Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence
Ohtani, N., Zebedee, Z., Huot, T. J. G., Stinson, J. A., Sugimoto, M., Ohashi, Y., Sharrocks, A. D., Peters, G., & Hara, E. (2001) · Nature · doi:10.1038/35059131 · Cited by 654
Targeted disruption of the three Rb-related genes leads to loss of G 1 control and immortalization
Sage, J., Mulligan, G. J., Attardi, L. D., Miller, A., Chen, S., Williams, B., Theodorou, E., & Jacks, T. (2000) · Genes & Development · doi:10.1101/gad.843200 · Cited by 582
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice
Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A., & Berns, A. (2001) · Nature · doi:10.1038/35092584 · Cited by 568
twist is a potential oncogene that inhibits apoptosis
Maestro, R., Tos, A. P. D., Hamamori, Y., Krasnokutsky, S., Sartorelli, V., Kedes, L., Doglioni, C., Beach, D. H., & Hannon, G. J. (1999) · Genes & Development · doi:10.1101/gad.13.17.2207 · Cited by 516
Different telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482
Dissecting p53 tumor suppressor functions in vivo
Schmitt, C. A., Fridman, J. S., Yang, M., Baranov, E., Hoffman, R. M., & Lowe, S. W. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00047-8 · Cited by 481
Self-citationINK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R., & Lowe, S. W. (1999) · Genes & Development · doi:10.1101/gad.13.20.2670 · Cited by 458
Self-citationPutative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions
Ramirez, R. D., Morales, C. P., Herbert, B.-S., Rohde, J. M., Passons, C., Shay, J. W., & Wright, W. E. (2001) · Genes & Development · doi:10.1101/gad.859201 · Cited by 444
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413
Wright, W. E., & Shay, J. W. (2000) · Nature Medicine · doi:10.1038/78592 · Cited by 398
Jacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., et al. (2000) · Nature Genetics · doi:10.1038/81583 · Cited by 368
p53-independent functions of the p19ARF tumor suppressorPreprint
Weber, J. D., Jeffers, J. R., Rehg, J. E., Randle, D. H., Lozano, G., Roussel, M. F., Sherr, C. J., & Zambetti, G. P. (2000) · Genes & Development · doi:10.1101/gad.827300 · Cited by 361
Self-citationOpposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357
JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression
Passegue, E. A., & Wagner, E. F. (2000) · The EMBO Journal · doi:10.1093/emboj/19.12.2969 · Cited by 333
Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction
Mullen, A. C., Hutchins, A. S., High, F. A., Lee, H. W., Sykes, K. J., Chodosh, L. A., & Reiner, S. L. (2002) · Nature Immunology · doi:10.1038/ni807 · Cited by 308
p16INK4A and p19ARF act in overlapping pathways in cellular immortalization
Carnero, A., Hudson, J. D., Price, C. M., & Beach, D. (2000) · Nature Cell Biology · doi:10.1038/35004020 · Cited by 280
Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a
Alani, R. M., Young, A. Z., & Shifflett, C. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141235398 · Cited by 231
Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice
Lund, A. H., Turner, G., Trubetskoy, A., Verhoeven, E., Wientjens, E., Hulsman, D., Russell, R. G., DePinho, R. A., Lenz, J., & van Lohuizen, M. (2002) · Nature Genetics · doi:10.1038/ng956 · Cited by 229
Lack of Replicative Senescence in Cultured Rat Oligodendrocyte Precursor Cells
Tang, D. G., Tokumoto, Y. M., Apperly, J. A., Lloyd, A. C., & RAFF, M. C. (2001) · Science · doi:10.1126/science.1056780 · Cited by 227
INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence
Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P. A., Lomax, M., James, M. C., Vatcheva, R., Bates, S., Vousden, K. H., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf289 · Cited by 220
Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation
Lin, A. W., & Lowe, S. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091100298 · Cited by 215
Self-citationPantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201
Lack of Replicative Senescence in Normal Rodent Glia
Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L., & Lloyd, A. C. (2001) · Science · doi:10.1126/science.1056782 · Cited by 183
Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas
Bardeesy, N., Bastian, B. C., Hezel, A., Pinkel, D., DePinho, R. A., & Chin, L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.6.2144-2153.2001 · Cited by 166
Zou, 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
Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice
You, M. J., Castrillón, D. H., Bastian, B. C., O’Hagan, R. C., Bosenberg, M., Parsons, R. E., Chin, L., & DePinho, R. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.022632099 · Cited by 143
Holland, E. C., Hively, W. P., Gallo, V., & VARMUS, H. E. (1998) · Genes & Development · doi:10.1101/gad.12.23.3644 · Cited by 124
The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development
McKeller, R. N., Fowler, J. L., Cunningham, J. J., Warner, N., Smeyne, R. J., Zindy, F., & Skapek, S. X. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052484199 · Cited by 120
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
A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells
Coats, S., Whyte, P., Fero, M. L., Lacy, S. E., Chung, G., Randel, E., Firpo, E. J., & Roberts, J. M. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80086-4 · Cited by 117
Muraoka, R. S., Lenferink, A. E. G., Law, B. K., Hamilton, E., Brantley, D. M., Roebuck, L. R., & Arteaga, C. L. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.7.2204-2219.2002 · Cited by 116
Randle, D. H., Zindy, F., Sherr, C. J., & Roussel, M. F. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171217498 · Cited by 108
Self-citationSuppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry
Lomazzi, M., Moroni, M. C., Jensen, M. R., Frittoli, E., & Helin, K. (2002) · Nature Genetics · doi:10.1038/ng891 · Cited by 85
Shay, J. W., & Wright, W. E. (2001) · Science · doi:10.1126/science.1058546 · Cited by 83
p16(INK4a) and p53 deficiency cooperate in tumorigenesis.
Sharpless, N. E., Alson, S., Chan, S., Silver, D. P., Castrillón, D. H., & DePinho, R. A. (2002) · PubMed · Cited by 63
Modestou, M., Puig-Antich, V., Korgaonkar, C. K., Eapen, A. K., & Quelle, D. E. (2001) · PubMed · Cited by 44
Hanahan, D. (2000) · Nature · doi:10.1038/35020662 · Cited by 39
Cited by
Sorted by citations
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302
“cancer risk [12,13].”
Cancer stem cells in solid tumours: accumulating evidence and unresolved questions
Visvader, J. E., & Lindeman, G. J. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2499 · Cited by 3,501
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
“…or both. the cell cycle inhibitor p16. p16 is a positive regulator of pRB and tumor suppressor in its own right (Sherr and McCormick, 2002). p16 is induced by a variety of stressful stimuli, including overexpression of oncogenes such as RAS and suboptimal culture conditions (Lowe and Sherr, 2003).”
BackgroundRb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278
Self-citation
Metadata
- Authors
- Lowe, S. W., & Sherr, C. J.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Lowe, Scott W
- Sherr, Charles J
- Venue
- Current Opinion in Genetics & Development
- Publisher
- Elsevier BV
- Published
- 2003-02
- Volume
- 13
- Issue
- 1
- Pages
- 77-83
- ISSN
- 0959-437X (ISSN-L)
- OpenAlex
- W1984948591
- Cited by
- 699
- References
- 56
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 20 · 2022: 10 · 2021: 5 · 2020: 10 · 2019: 15 · 2018: 10 · 2017: 17 · 2016: 17 · 2015: 29 · 2014: 30 · 2013: 48 · 2012: 34
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Genetics & Development (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- 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
- INK4a/ARF locus, p16INK4a, p19ARF, tumor suppression, retinoblastoma protein, p53, stress signaling, cell proliferation, tumor onset, mouse tumor model, drug response
- MeSH terms
- Animals, Humans, Lymphoma, Neoplasms, Tumor Suppressor Protein p53, Retinoblastoma Protein, Cyclin-Dependent Kinase Inhibitor p16, ADP-Ribosylation Factors, Feedback, Physiological, Mice, Rats
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
