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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“Since the INK4a/ARF locus is an upstream regulator of both pRB and p53 (reviewed in Lowe and Sherr, 2003; Sharpless, 2005), vari ous mutations in this locus presumably can also substitute SV40 large T function in transformation assays, albeit at a lower efficiency depending on the nature of the…”
BackgroundZeb1 links epithelial-mesenchymal transition and cellular senescence
Liu, Y., El‐Naggar, S., Darling, D. S., Higashi, Y., & Dean, D. C. (2008) · Development · doi:10.1242/dev.007047 · Cited by 312
“It is of note that normal replicative senescence of wild-type MEFs results from time-dependent induction of the Ink4a locus in culture (usually leading to senescence around P10-12) (Lowe and Sherr, 2003; Gil and Peters, 2006).”
BackgroundResultExpression of p16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer
Konecny, G. E., Winterhoff, B. J. N., Kolarova, T. R., Qi, J., Manivong, K., Dering, J., Yang, G., Chalukya, M., Wang, H.-J., Anderson, L. A., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2307 · Cited by 303
“Activated p16 signaling drives premature and replicative senescence by inhibiting CDK4/6 and ultimately blocking cell cycle progression (25, 26).”
Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia
Chen, Y., Hu, Y., Zhang, H., Peng, C., & Li, S. (2009) · Nature Genetics · doi:10.1038/ng.389 · Cited by 297
Nucleophosmin (B23) Targets ARF to Nucleoli and Inhibits Its Function
Korgaonkar, C. K., Hagen, J., Tompkins, V. S., Frazier, A. A., Allamargot, C., Quelle, F. W., & Quelle, D. E. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.4.1258-1271.2005 · Cited by 294
“Rather, most of the evidence suggests that ARF specifically counters the development of oncogenically transformed cancer cells (43, 86).”
BackgroundPancreatic Cancer: Basic and Clinical Aspects
Schneider, G., Siveke, J. T., Eckel, F., & Schmid, R. M. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.04.001 · Cited by 289
Graux, C., Cools, J., Michaux, L., Vandenberghe, P., & Hagemeijer, A. (2006) · Leukemia · doi:10.1038/sj.leu.2404302 · Cited by 284
Kalin, T. V., Wang, I., Ackerson, T. J., Major, M. L., Detrisac, C. J., Kalinichenko, V. V., Lyubimov, A. V., & Costa, R. H. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3138 · Cited by 272
“Expression of ARF tumor suppressor is induced in response to oncogenic stimuli and prevents abnormal cell proliferation through stabilization of p53 tumor suppressor (6), yet expression of large T antigen, an inhibitor of both the p53 and Rb tumor suppressor proteins (18), in both TRAMP and LADY models would therefore…”
BackgroundMaclean, K. H., Dorsey, F. C., Cleveland, J. L., & Kastan, M. B. (2007) · Journal of Clinical Investigation · doi:10.1172/jci33700 · Cited by 281
Toward a Molecular Classification of Melanoma
Fecher, L. A., Cummings, S. D., Keefe, M. J., & Alani, R. M. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.06.0442 · Cited by 255
An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors
Chitale, D. A., Gong, Y., Taylor, B. S., Broderick, S., Brennan, C., Somwar, R., Golas, B., Wang, L., Motoi, N., Szőke, J., et al. (2009) · Oncogene · doi:10.1038/onc.2009.135 · Cited by 232
“…DUSP4 loss and EGFR mutation (or possibly other mutations activating the MAPK pathway) may drive selection for loss of the locus encoding p16CDKN2A and p14ARF, known mediators of senescence or apoptosis in response to inappropriate mitogenic signals (Lowe and Sherr 2003; Michaloglou et al. 2005).”
Role of Oxidative Stress in Stem, Cancer, and Cancer Stem Cells
Dayem, A. A., Choi, H.-Y., Kim, J., & Cho, S. (2010) · Cancers · doi:10.3390/cancers2020859 · Cited by 232
“(8) Metastasis: Both have the metastatic property; (9) Tumor suppressors: Tumor suppressors, such as p53, p16INK4a, and p19ARF inhibit cancer cell proliferation and stem cell self-renewal [26,27].”
BackgroundGenomic Instability and Cancer
Dai, Y. Y. W. (2014) · Journal of Carcinogenesis & Mutagenesis · doi:10.4172/2157-2518.1000165 · Cited by 264
“Arf is not usually expressed in normal tissues but is induced by sustained and elevated proliferation signals that may stem from oncogenic stress (Lowe and Sherr 2003).”
BackgroundThyroid cancer and inflammation
Guarino, V., Castellone, M. D., Avilla, E., & Melillo, R. M. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.10.003 · Cited by 233
A Short Mitochondrial Form of p19ARF Induces Autophagy and Caspase-Independent Cell Death
Reef, S., Zalckvar, E., Shifman, O., Bialik, S., Sabanay, H., Oren, M., & Kimchi, A. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.04.014 · Cited by 235
“, 2001) and is thus an important mediator in the activation of p53 in response to oncogenes (Lowe and Sherr, 2003).”
The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H., & DePinho, R. A. (2004) · Oncogene · doi:10.1038/sj.onc.1207074 · Cited by 224
“The Ink4a/Arf locus encodes two proteins, p16INK4a and p14ARF (p19ARF in the mouse), in overlapping reading frames which are commonly codeleted in a large variety of human cancers (reviewed in Lowe and Sherr 2003).”
BackgroundUbiquitination and Degradation of Mutant p53
Lukashchuk, N., & Vousden, K. H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-07 · Cited by 223
“It is possible that the stabilization of mutant p53 in tumors is related to the expression of ARF, an inhibitor of Mdm2 that is specifically activated in tumors (34).”
BackgroundImmunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis
Reid‐Nicholson, M. D., Iyengar, P., Hummer, A., Linkov, I., Asher, M., & Soslow, R. A. (2006) · Modern Pathology · doi:10.1038/modpathol.3800620 · Cited by 218
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
“(Lowe and Sherr, 2003; Serrano et al., 1995, 1996).”
Wang, Y., Probin, V., & Zhou, D. (2006) · Current Cancer Therapy Reviews · doi:10.2174/157339406777934717 · Cited by 217
“p16Ink4a binds to cyclin-dependent kinases (CDK) 4/6 to prevent their interaction with cyclin D and thus, inhibits CDK4/6 activity [75].”
BackgroundInfluentialMiller, S. J., Rangwala, F. A., Williams, J. P., Ackerman, P., Kong, S., Jegga, A. G., Kaiser, S., Aronow, B. J., Frahm, S., Kluwe, L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3330 · Cited by 207
Cellular responses to reactive oxygen species-induced DNA damage and aging
Bertram, C., & Hass, R. (2008) · Biological Chemistry · doi:10.1515/bc.2008.031 · Cited by 217
Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases
Colombo, E., Alcalay, M., & Pelicci, P. G. (2011) · Oncogene · doi:10.1038/onc.2010.646 · Cited by 223
Mechanisms controlling cell cycle exit upon terminal differentiation
Buttitta, L., & Edgar, B. A. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.10.004 · Cited by 200
Reactive oxygen species and hematopoietic stem cell senescence
Shao, L., Li, H., Pazhanisamy, S. K., Meng, A., Wang, Y., & Zhou, D. (2011) · International Journal of Hematology · doi:10.1007/s12185-011-0872-1 · Cited by 205
“HSCs from Bmi1−/− mice express increased levels of p16 and Arf [27, 57, 58].”
BackgroundInfluentialThe Quest for the 1p36 Tumor Suppressor
Bagchi, A., & Mills, A. A. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2095 · Cited by 196
Denchi, E. L., Attwooll, C., Pasini, D., & Helin, K. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2660-2672.2005 · Cited by 195
“To further substantiate this observation, we used two independent markers of senescence, p16 and p19 (26).”
MethodThe tumor-suppressive functions of the human INK4A locus
Voorhoeve, P. M., & Agami, R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00223-x · Cited by 194
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus
González, S., Klatt, P., Delgado, S., Conde, E., López‐Ríos, F., Sánchez‐Céspedes, M., Méndez, J., Antequera, F., & Serrano, M. (2006) · Nature · doi:10.1038/nature04585 · Cited by 186
RetractedCRL4B Catalyzes H2AK119 Monoubiquitination and Coordinates with PRC2 to Promote Tumorigenesis
Hu, H., Yang, Y., Ji, Q., Zhao, W., Jiang, B., Liu, R., Yuan, J., Liu, Q., Li, X., Zou, Y., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.024 · Cited by 185
“Regulation of p16 and PTEN by the CLR4B/PRC2 Complex Among the common target genes identified earlier, p16 and PTEN are well-established tumor suppressor genes (Lowe and Sherr, 2003; Salmena et al., 2008).”
BackgroundFOXM1 (Forkhead box M1) in Tumorigenesis
Wierstra, I. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00016-2 · Cited by 190
Rachmian, N., Medina, S., Cherqui, U., Akiva, H., Deitch, D., Edilbi, D., Croese, T., Salame, T., Ramos, J. M. P., Cahalon, L., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01620-8 · Cited by 196
Regulating the p53 system through ubiquitination
Yang, Y., Li, C.-C. H., & Weissman, A. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207411 · Cited by 184
“Notably, overexpression of Mdm2 occurs in about 10% of human tumors and loss of ARF is found in even more tumor cells (Lowe and Sherr, 2003).”
Backgroundp53 and NF‐κB: different strategies for responding to stress lead to a functional antagonism
Ak, P., & Levine, A. J. (2010) · The FASEB Journal · doi:10.1096/fj.10-160549 · Cited by 188
“Similarly, mutations that activate several oncogenes (Ras and myc) increase ARF levels and activate p53 (9).”
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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