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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p53-Dependent and -Independent Functions of the Arf Tumor SuppressorPreprint
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“Instead, their induction occurs in response to particular cellular stresses that can contribute to tumor formation (Lowe and Sherr 2003).”
BackgroundSelf-citationTranscriptional and epigenetic regulation of the p53 tumor suppressor gene
Saldaña-Meyer, R., & Targa, F. R. (2011) · Epigenetics · doi:10.4161/epi.6.9.16683 · Cited by 103
“For example, upon cellular stress E2F1 and p53 are activated and stabilized to induce apoptosis through common regulators like the CDKN2A locus and the p300 and PCAF acetylases.(33,34) Also, increased nuclear p53 has been observed when E2F1 directly binds to p53 phosphorylated at Ser315 improving p53’s DNA binding and…”
BackgroundTargeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis
Paliwal, S., Pande, S., Kovi, R. C., Sharpless, N. E., Bardeesy, N. M., & Grossman, S. R. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.6.2360-2372.2006 · Cited by 104
“ARF exerts tumor suppression functions utilizing both p53dependent and -independent pathways (27, 48, 57).”
BackgroundInfluentialProtein p16 as a marker of dysplastic and neoplastic alterations in cervical epithelial cells
Волгарева, Г. М., Эдуардовна, З. Л., Andreeva, Y. Y., Frank, G. A., Крутікова, Е. І., Golovina, D., Bliev, A., Spitkovsky, D., Ermilova, V. D., & Kisseljov, F. L. (2004) · BMC Cancer · doi:10.1186/1471-2407-4-58 · Cited by 100
“Functionally active gene RB was shown to be able to negatively regulate the expression of INK4a on a transcriptional level, but details of this negative feed-back loop remain obscure [24].”
BackgroundTime- and dose-dependent effects of curcumin on gene expression in human colon cancer cells.
van Erk, M. J., Teuling, E., Staal, Y. C. M., Huybers, S., van BLADEREN, P. J., Aarts, J. M. M. J. G., & van Ommen, B. (2004) · Journal of Carcinogenesis · doi:10.1186/1477-3163-3-8 · Cited by 99
Disruption of the Rb-Raf-1 Interaction Inhibits Tumor Growth and Angiogenesis
Dasgupta, P., Sun, J., Wang, S., Fusaro, G., Betts, V., Padmanabhan, J., Sebti, S. M., & Chellappan, S. P. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9527-9541.2004 · Cited by 98
“Cotransfection of Raf-1 effectively inactivated Rb, relieving Rb-mediated repression of E2F1; but cotransfection of cdk inhibitor p16INK4 (35) or p21 (42) had no effect on Raf-1-mediated inactivation of Rb function.”
BackgroundTranscriptional regulation of cellular senescence
Lanigan, F., Geraghty, J. G., & Bracken, A. P. (2011) · Oncogene · doi:10.1038/onc.2011.34 · Cited by 95
“Molecular pathways controlling cellular senescence The retinoblastoma protein (pRb) and p53 tumour suppressor pathways represent the core signalling pathways involved in the induction of cellular senescence (Lowe and Sherr, 2003; Narita and Lowe, 2005; Collado and Serrano, 2010).”
Fbw7 and p53 Cooperatively Suppress Advanced and Chromosomally Unstable Intestinal Cancer
Grim, J. E., Knoblaugh, S. E., Guthrie, K. A., Hagar, A., Swanger, J., Hespelt, J., Delrow, J. J., Small, T., Grady, W. M., Nakayama, K. I., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00305-12 · Cited by 97
“p53 activation is a homeostatic response that protects cells against deregulated oncogenes, including the cyclin E and Myc genes, and p53 is activated by Fbw7 pathway mutations (17, 18, 25).”
Backgroundp16INK4a Expression, human papillomavirus, and survival in head and neck cancer
Smith, E., Wang, D., Kim, Y., Rubenstein, L. M., Lee, J. H., Haugen, T. H., & Turek, L. P. (2007) · Oral Oncology · doi:10.1016/j.oraloncology.2007.01.010 · Cited by 97
Chapman, E., Hurst, C. D., Pitt, E., Chambers, P. A., Aveyard, J. S., & Knowles, M. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209513 · Cited by 95
“The roles of the CDKN2A genes differ in mouse and man (Lowe and Sherr, 2003), so Received 23 June 2005; revised 7 February 2006; accepted 15 February 2006; published online 17 April 2006 Correspondence: Dr MA Knowles, Cancer Research UK Clinical Centre, St James’s University Hospital, Beckett…”
BackgroundRegulation of Programmed Cell Death by the P53 Pathway
Kuribayashi, K., & El‐Deiry, W. S. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-1-4020-6554-5_10 · Cited by 95
Emerging roles of RB family: New defense mechanisms against tumor progression
Indovina, P., Marcelli, E., Casini, N., Rizzo, V., & Giordano, A. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24170 · Cited by 95
“The expression of p16 is induced by oncogenes and a variety of stressful stimuli (Lowe and Sherr, 2003).”
BackgroundEarly Vascular Ageing and Cellular Senescence in Chronic Kidney Disease
Dai, L., Qureshi, A. R., Witasp, A., Lindholm, B., & Stenvinkel, P. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.06.015 · Cited by 98
“Thus, the activation p16/pRB pathway is essentially irreversible and it is primarily triggered by oncogene mutations and various stress [47].”
BackgroundLaine, H., Doetzlhofer, A., Mantela, J., Ylikoski, J. S., Laiho, M., Roussel, M. F., Segil, N., & Pirvola, U. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4956-06.2007 · Cited by 96
Montanaro, L., Treré, D., & Derenzini, M. (2011) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2011.10.006 · Cited by 98
“The ARF gene may be mutated or silenced in tumor cells [52, 53], and the loss of p14ARF expression may be responsible for the enhancement of ribosome biogenesis both directly and through the action on p53 stabilization.”
BackgroundNucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization
Saxena, A. D., Rorie, C. J., Dimitrova, D. D., Daniely, Y., & Borowiec, J. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209714 · Cited by 94
“One prominent member of this group is the ARF tumor suppressor (p14ARF in humans, p19ARF in mice) (Lowe and Sherr, 2003).”
BackgroundLiu, Y., Clem, B. F., Zuba‐Surma, E. K., El‐Naggar, S., Telang, S., Jenson, A. B., Wang, Y., Shao, H., Ratajczak, M. Z., Chesney, J. A., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.02.015 · Cited by 96
“Moreover, the RB1 family is regulated by phosphorylation mediated by cdks, and in tumors where RB1 is not mutated the pathway is inactivated by hyperphosphorylation of family members (Kaye, 2002; Du and Pogoriler, 2006; Frolov and Dyson, 2004; Lowe and Sherr, 2003).”
BackgroundBMI-1, a promising therapeutic target for human cancer
Wang, M., Li, C., Cui, J., Jiao, M., Wu, T., Li, J., & Nan, K. (2015) · Oncology Letters · doi:10.3892/ol.2015.3361 · Cited by 96
“In addition, p16 Ink4a and p19 Arf restrain cell proliferation by partly overlapping signaling pathways that control the cell cycle, cell differentiation, senescence and survival (57,73,74).”
Update on the molecular biology of malignant mesothelioma
Lee, A. Y., Raz, D. J., He, B., & Jablons, D. M. (2007) · Cancer · doi:10.1002/cncr.22552 · Cited by 92
“p14ARF acts by directly binding to and promoting the degradation of Mdm2, thus leading to the stabilization of p53.(39) Therefore, a single mutational event at the INK4a/ARF locus has the potential to disrupt both of these 2 key growth control pathways.”
BackgroundPrognostic value of Bmi-1 oncoprotein expression in NSCLC patients: a tissue microarray study
Vrzalikova, K., Škarda, J., Ehrmann, J., Murray, P. G., Fridman, E., Kopolovic, J., Hamerlik, P., Hajdúch, M., Klein, J., Kolek, V., et al. (2008) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-008-0361-y · Cited by 90
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“Elegant studies from the Lowe and Campisi labs have shown that Rb is hypophosphorylated in senescent cells, and its function is necessary for inducing the senescent phenotype (5, 31).”
BackgroundKawano, Y., Nasu, K., Li, H., Tsuno, A., Abe, W., Takai, N., & Narahara, H. (2011) · Human Reproduction · doi:10.1093/humrep/der203 · Cited by 88
Development and translational imaging of a TP53 porcine tumorigenesis model
Sieren, J. C., Meyerholz, D. K., Wang, X., Davis, B. T., Newell, J. D., Hammond, E., Rohret, J. A., Rohret, F., Struzynski, J. T., Goeken, J. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75447 · Cited by 88
“It is estimated that p53 function is compromised in the vast majority of human tumors, through either TP53 gene mutation or alterations targeting the numerous regulators of p53 signaling (11–14).”
BackgroundMullighan, C. G., Williams, R. T., Downing, J. R., & Sherr, C. J. (2008) · Genes & Development · doi:10.1101/gad.1673908 · Cited by 88
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Cudré-Mauroux, C., Occhiodoro, T., König, S., Salmon, P., Bernheim, L., & Trono, D. (2003) · Human Gene Therapy · doi:10.1089/104303403322495034 · Cited by 86
Cellular Senescence in the Development and Treatment of Cancer
Saretzki, G. C. (2009) · Current Pharmaceutical Design · doi:10.2174/138161210789941874 · Cited by 92
“However, this pathway is apparently not conserved in human cells [45].”
BackgroundRibosomal proteins as novel players in tumorigenesis
Heras-Rubio, A. D. L., Perucho, L., Paciucci, R., Vilardell, J., & LLeonart, M. E. (2013) · Cancer and Metastasis Reviews · doi:10.1007/s10555-013-9460-6 · Cited by 87
Jerome‐Majewska, L. A., Jenkins, G. P., Ernstoff, E., Zindy, F., Sherr, C. J., & Papaioannou, V. E. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20575 · Cited by 86
“Although numerous experiments support the view that p19Arf is a potent modulator of the p53-induced transcriptional program, p19Arf also exerts its effects on the cell cycle through alternative p53-independent programs that are as yet poorly understood (Lowe and Sherr, 2003).”
BackgroundSelf-citationVersatile functions of p53 protein in multicellular organisms
Chumakov, P. M. (2007) · Biochemistry (Moscow) · doi:10.1134/s0006297907130019 · Cited by 85
The Role of Tbx2 and Tbx3 in Mammary Development and Tumorigenesis
Rowley, M., Grothey, E., & Couch, F. J. (2004) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/b:jomg.0000037156.64331.3f · Cited by 97
Distinct E2F‐mediated transcriptional program regulates p14 ARF gene expression
Komori, H., Enomoto, M., Nakamura, M., Iwanaga, R., & Ohtani, K. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600836 · Cited by 86
“The p14ARF protein is thought to play a crucial role in tumor suppression against oncogenic cell growth induced by ectopically expressed E2F (Lowe and Sherr, 2003).”
BackgroundInfluentialLinggi, M. S., Burke, T. L., Williams, B. B., Harrington, A., Kraemer, R. T., Hempstead, B. L., Yoon, S. O., & Carter, B. D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410435200 · Cited by 83
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“2C, D), p16Ink4a and p19Arf are induced in culture in neural stem cells (Molofsky et al., 2003) in response to the stress associated with adaptation to the unphysiological culture environment (Lowe and Sherr, 2003; Sherr and DePinho, 2000).”
BackgroundKelly‐Spratt, K. S., Gurley, K. E., Yasui, Y., & Kemp, C. J. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020242 · Cited by 84
“Cell culture conditions can add additional stress signals that are known to impinge on p19Arf and p53, leading to cell cycle arrest (Sherr and DePinho 2000; Lowe and Sherr 2003), and cannot recapitulate the complex cellular ecology of tumor progression.”
BackgroundZhou, L., Zhang, X., He, M., Cheng, L., Chen, Y., Hu, F. B., & Wu, T. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.176065 · Cited by 82
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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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