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.
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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]
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“Seventy-two hours following transduction, relative expression levels of INK4b, ARF and INK4a were determined by RT-qPCR of isolated mRNA.”
BackgroundInfluentialThe nuclear envelope can control gene expression and cell cycle progression via miRNA regulation
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“p16 is an inhibitor of cyclin D-dependent kinases which regulate the retinoblastoma protein (pRb) pathway while p19 regulates cell cycle progression through p53.(17) Expression of p16 and p19 (p14 in humans) are altered by deletion, mutation or promoter methylation of the INK4a-Arf locus in about 40% of cancers.”
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Quiroz, E. N., Quiroz, R. N., Ahmad, M., Escorcia, L. G., Camacho, J. L. V., Fernandez-Ponce, C. M., & Aroca, G. (2018) · Cells · doi:10.3390/cells7070075 · Cited by 55
“In addition, Bmi-1 represses transcription at the Ink4a-Arf locus [25], encodes two inhibitors of cell proliferation [26], Ink4a encodes p16 Ink4a, an inhibitor of cyclin-dependent kinase that promotes activation of Rb, the Arf encodes p19 Arf, which promotes the activation of p53, p16 Ink4a, and p19 Arf induced in cu…”
BackgroundMaurelli, R., Zambruno, G., Guerra, L., Abbruzzese, C., Dimri, G. P., Gellini, M., Bondanza, S., & Dellambra, E. (2006) · The FASEB Journal · doi:10.1096/fj.05-4480fje · Cited by 54
“cancers by genetic and epigenetic mechanisms (47).”
BackgroundAn ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis
Kovi, R. C., Paliwal, S., Pande, S., & Grossman, S. R. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.140 · Cited by 53
“normal cells and is induced mainly by oncogenic, and not environmental, stress signals.(2,4) However, the ability of ARF to inhibit CtBP might potentiate the apoptotic affect of”
BackgroundPolycomb Group Proteins Are Key Regulators of Keratinocyte Function
Eckert, R. L., Adhikary, G., Rorke, E. A., Chew, Y. C., & Balasubramanian, S. (2010) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.318 · Cited by 55
Life, Death, and Ubiquitin: Taming the Mule
Shmueli, A., & Oren, M. (2005) · Cell · doi:10.1016/j.cell.2005.06.018 · Cited by 53
Han, J., Tsukada, Y.-I., Hara, E., Kitamura, N., & Tanaka, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503431200 · Cited by 52
Khoo, C. M., Carrasco, D. R., Bosenberg, M. W., Paik, J.-H., & DePinho, R. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700093104 · Cited by 52
Ellis, K. L., Pilbrow, A. P., Frampton, C. M., Doughty, R. N., WHALLEY, G. A., Ellis, C., Palmer, B. R., Skelton, L., Yandle, T. G., Palmer, S. C., et al. (2010) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.109.917443 · Cited by 52
MicroRNA-203 enhances Coxsackievirus B3 replication through targeting zinc finger protein-148
Hemida, M. G., Ye, X., Zhang, H. M., Hanson, P., Liu, Z., McManus, B. M., & Yang, D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1104-4 · Cited by 51
“of the downstream genes of ZFP-148 involved in cell cycle regulation, which include cyclin-dependent kinase inhibitors (p21 and, p27), tumor suppressors [retinoblastoma (Rb) and p53] and cell cycle progression genes (cyclin E and cyclin D1) [27, 28], in pre-miR-203-transfected HeLa cells infected with CVB3 or sham-inf…”
BackgroundAn Inducible Mouse Model of Melanoma Expressing a Defined Tumor Antigen
Huijbers, I. J., Krimpenfort, P., Chomez, P., van der Valk, M. A., Song, J., Inderberg, E. M., Schmitt‐Verhulst, A., Berns, A. J. M., & den Eynde, B. J. V. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3216 · Cited by 50
“INK4a/ARF contains two overlapping reading frames, which encode two tumor suppressor proteins, p16 and p14 (p19 in mouse), which exert their functions via distinct pathways (17).”
Khan, F. S., Ali, I., Afridi, U. K., Ishtiaq, M., & Mehmood, R. (2016) · Hepatology International · doi:10.1007/s12072-016-9743-4 · Cited by 52
“The p16 protein is a critical cell cycle regulator that is encoded by the inhibitor of cyclin-dependent kinase (CDK) 4 (INK4A) gene [97, 98].”
BackgroundFunctions of Myc:Max in the Control of Cell Proliferation and Tumorigenesis
Hurlin, P. J., & Dezfouli, S. (2004) · International review of cytology · doi:10.1016/s0074-7696(04)38004-6 · Cited by 54
Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells
Kwok, W. K., Ling, M. T., Yuen, H., Wong, Y. C., & Wang, X. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm185 · Cited by 56
Stem Cells Use Distinct Self-renewal Programs at Different AgesPreprint
Levi, B. P., & Morrison, S. J. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.049 · Cited by 54
“…is a cyclin-dependent kinase inhibitor that promotes Rb (retinoblastoma) activation, slowing cell cycle progression or inducing cellular senescence (Lowe and Sherr 2003). p19Arf promotes p53 activity, also slowing cell cycle progression or inducing cellular senescence. p16Ink4a and p19Arf…”
BackgroundLindström, M. S., & Zhang, Y. (2006) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:46:1:79 · Cited by 52
“ARF-specific mutations have been reported (65), but most mutations target both p14ARF and p16INK4A efficiently disabling two tumor proteins with a single hit (64).”
BackgroundQi, D.-L., & Cobrinik, D. E. (2016) · Oncogene · doi:10.1038/onc.2016.350 · Cited by 51
“15 In most cancers, this surveillance circuitry is impaired by TP53 mutation, CDKN2A ARF inactivation, or MDM2 amplification.”
Recent Advances in Validating MDM2 as a Cancer Target
Rayburn, E. R., Ezell, S. J., & Zhang, R. (2009) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152009789124628 · Cited by 50
Fosmire, S. P., Thomas, R. J., Jubala, C. M., Wojcieszyn, J. W., Valli, V. E., Getzy, D. M., Smith, T. L., Gardner, L. A., Ritt, M. G., Bell, J. S., et al. (2007) · Veterinary Pathology · doi:10.1354/vp.44-4-467 · Cited by 49
p53-Induced Apoptosis Occurs in the Absence of p14ARF in Malignant Pleural Mesothelioma
Hopkins-Donaldson, S., Belyanskaya, A. L., Simões‐Wüst, A. P., Sigrist, B., Kurtz, S., Zangemeister‐Wittke, U., & Stahel, R. A. (2006) · Neoplasia · doi:10.1593/neo.06148 · Cited by 47
“expression has also been described to play a role in the response of p53 to DNA damage [9,10], although these results are controversial [11,12].”
BackgroundResultSubkhankulova, T., Zhang, X., Leung, C., & Marino, S. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.06.006 · Cited by 50
Richardson, M., & Richardson, D. R. (2023) · Molecular Pharmacology · doi:10.1124/molpharm.123.000803 · Cited by 48
Yang, J., Gu, L., Guo, X., Huang, J., Chen, Z., Huang, G., Kang, Y., Zhang, X., Long, J., & Su, L. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0593-6 · Cited by 47
“The CDKN2A and CDKN2B genes, which are located near to or overlapping with ANRIL in chromosome 9p21, play a critical inhibitory role in the cell cycle, apoptosis, cell proliferation, and cell senescence (Gil and Peters 2006; Lowe and Sherr 2003).”
BackgroundMelanoma Biology and the Promise of Zebrafish
Ceol, C. J., Houvras, Y. J., White, R. M., & Zon, L. I. (2008) · Zebrafish · doi:10.1089/zeb.2008.0544 · Cited by 47
“CDKN2A is a complex locus that encodes the INK4A and ARF tumor suppressor genes.(88) Each of these genes begins with its own coding sequence, but downstream exons are shared.”
Liu, Y., Sànchez‐Tilló, E., Lu, X., Huang, L. F., Clem, B. F., Telang, S., Jenson, A. B., Cuatrecasas, M., Chesney, J. A., Postigo, A. A., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.533505 · Cited by 49
“Chronic stimulation of Ras signaling by serum growth factors in cell culture likewise leads to senescence, but only after multiple passages (13, 34, 35) (Fig.”
BackgroundHwang, Y.-C., Lu, T., Huang, D., Kuo, Y., Kao, C.-F., Yeh, N.-H., Wu, H., & Lin, C. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080931 · Cited by 46
“ARF has been reported to be able to induce TP53 transcriptional activity by binding and inactivating MDM2, 52–54 and in NPC there is often decreased expression of ARF protein 23,54,55 We found no difference in ARF expression between the shNOLC1 transfected and non-transfected NPC-TW03 xenografts (data not shown).”
BackgroundInfluentialvan Galen, J. C., Muris, J. J. F., Oudejans, J. J., Vos, W., Giroth, C., Ossenkoppele, G. J., Otte, A. P., Raaphorst, F. M., & Meijer, C. J. L. M. (2006) · Journal of Clinical Pathology · doi:10.1136/jcp.2006.038752 · Cited by 50
Critical role of the Polycomb and Trithorax complexes in the maintenance of CD4 T cell memory
Nakayama, T., & Yamashita, M. (2009) · Seminars in Immunology · doi:10.1016/j.smim.2009.02.001 · Cited by 45
Epigenetic Regulation of Hematopoietic Stem Cell Self-Renewal by Polycomb Group Genes
Iwama, A., Oguro, H., Negishi, M., Kato, Y., & Nakauchi, H. (2005) · International Journal of Hematology · doi:10.1532/ijh97.05011 · Cited by 46
Zeng, Z., Richardson, J., Verduzco, D., Mitchell, D. L., & Patton, E. E. (2009) · Zebrafish · doi:10.1089/zeb.2009.0611 · Cited by 45
“57 61 In mice, HRAS mutations in a p53-null background cause melanoma, 62 and in zebrafish, p53 mutations can contribute to the promotion of BRAF V600E melanocytic nevi to malignant melanoma.”
Chang, H., Yeung, J., Qi, C. X. Y., & Xu, W. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06649.x · Cited by 45
“One of the major factors contributing to p53 stabilisation is via expression of p14ARF (Lowe & Sherr, 2003).”
BackgroundSolomon, D. A., Kim, J.-S., Jean, W. C., & Waldman, T. A. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2084 · Cited by 45
“which modulates the activity of the p53 tumor suppressor (4, 5).”
Hasan, M. K., Yaguchi, T., MINODA, Y., Hirano, T., Taira, K., Wadhwa, R., & Kaul, S. C. (2004) · Biochemical Journal · doi:10.1042/bj20040337 · Cited by 45
Bmi-1 regulates self-renewal, proliferation and senescence of human fetal neural stem cells in vitro
Wang, Y., Guan, Y., Wang, F., Huang, A., Wang, S., & Zhang, Y. A. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.04.006 · Cited by 47
Cooperative Role of the RNA-Binding Proteins Hzf and HuR in p53 Activation
Nakamura, H., Kawagishi, H., Watanabe, A., Sugimoto, K., Maruyama, M., & Sugimoto, M. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01424-10 · Cited by 45
“Aberrant growth signaling caused by oncogenes induces the expression of the tumor suppressor protein p19 (p14 in humans), which binds to Mdm2 and antagonizes its E3 ubiquitin ligase activity, thereby stabilizing p53 protein (30).”
BackgroundEl‐Naggar, S., Liu, Y., & Dean, D. C. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00197-09 · Cited by 44
“One target of the increase in cyclin-dependent kinase (cdk) activity resulting from Erk-dependent induction of genes such as the one encoding cyclin D1 is the Rb1 pathway, whose family members are hyperphosphorylated and inactivated by the resulting accumulation of cdk activity (13, 25).”
BackgroundTargeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer
Dahl, E. S., Buj, R., Leon, K. E., Newell, J. M., Kawasawa, Y. I., Bitler, B. G., Snyder, N. W., & Aird, K. M. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-1233 · Cited by 44
Hemmati, P., Güner, D., Gillissen, B. F., Wendt, J., von Haefen, C., Chinnadurai, G., Dörken, B., & Daniel, P. T. (2006) · Oncogene · doi:10.1038/sj.onc.1209668 · Cited by 44
“By linking the Rb and p53 signaling pathways, ARF plays a central role in monitoring cellular proliferation (Lowe and Sherr, 2003).”
BackgroundAyrault, O., Andrique, L., Larsen, C., & Seité, P. (2004) · Oncogene · doi:10.1038/sj.onc.1207968 · Cited by 44
“The Arf protein (p14ARF in man and p19ARF in mouse) is one of the two tumor suppressor proteins encoded by the p16INK4a/CDKN2 gene located on chromosome 9p21 in man (for a review see Lowe and Sherr, 2003).”
BackgroundIdentification of Novel ARF Binding Proteins by Two-Hybrid Screening
Tompkins, V. S., Hagen, J., Zediak, V. P., & Quelle, D. E. (2006) · Cell Cycle · doi:10.4161/cc.5.6.2560 · Cited by 43
Regulation of Stem Cell Differentiation by Histone Methyltransferases and DemethylasesPreprint
Pasini, D., Bracken, A. P., Agger, K., Christensen, J. F., Hansen, K. H., Cloos, P. A., & Helin, K. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.009 · Cited by 45
“Elevated levels of both p16INK4A and p14ARF expression lead to cell cycle arrest (Sherr 1998; Lowe and Sherr 2003).”
Background
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
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