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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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Detection of aberrant methylation of tumor suppressor genes in plasma from cancer patients
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“The tumor suppressor gene p14ARF encodes an alternate reading frame product of the p16INK4a locus on chromosome 9p21 [35,36].”
BackgroundSenescence program and its reprogramming in pancreatic premalignancy
Yang, K., Li, X., & Xie, K. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06040-3 · Cited by 20
Notch1 signaling contributes to the oncogenic effect of HBx on human hepatic cells
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Aging of the inceptive cellular population: the relationship between stem cells and aging
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“triggering of the senescence pathway [77].”
Prognostic impact ofp15gene aberrations in acute leukemia
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“apoptosis.[12,13] p15 acts as an effector of transforming growth fac-”
BackgroundZhang, C., Guo, X., Zhang, L., Lu, Z., Ma, N., Cheng, Y., Shen, F., Zhang, B., Wu, M., & Wei, L. (2008) · Journal of Surgical Oncology · doi:10.1002/jso.21131 · Cited by 15
“The p14 tumor suppressor, in response to oncogenic and hyperproliferative signals as well as signals of DNA damage, binds to MDM2 and consequently activates p53 by blocking nuclear export of p53 and MDM2 and thus blocking p53 degradation [31].”
BackgroundPark (2009) · International Journal of Oncology · doi:10.3892/ijo_00000294 · Cited by 15
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“Perhaps the 2 most commonly altered pathways in the vast preponderance of human tumors are those associated with P53 (P53, mdm2, ARF) and with Rb (RB, P16, P14, P21, cyclin D1, cyclin E) [21, 22].”
BackgroundDissecting Roles of Ubiquitination in the p53 Pathway
Shan, J., Brooks, C. L., Kon, N., Li, M., & Gu, W. J. (2008) · Ernst Schering Research Foundation workshop/Ernst Schering Foundation Symposium proceedings · doi:10.1007/2789_2008_105 · Cited by 15
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“suppressor pathway [4,5] which has been considered to function largely independent of the ATM-mediated DNA damage pathway.”
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“Recently, several genome-wide association studies have implicated chromosome region 9p21 as a novel locus that confers susceptibility to coronary artery disease (CAD) and MI in multiple white and Asian cohorts.(1-6) Two single-nucleotide polymorphisms (SNPs), rs10757274 and rs2383206, were initially identified by McPh…”
BackgroundARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis
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“Inhibition rather than induction of p53-dependent apoptosis by ARF is a unique feature of male germ cells and reveals an opposite to the well-established p53-mediated pro-apoptotic role of ARF in somatic cells (Lowe and Sherr, 2003).”
BackgroundInfluentialCell cycle genes co-expression in multiple myeloma and plasma cell leukemia
Kryukov, F., Dementyeva, E., Kubiczková, L., Jarkovský, J., Brožová, L., Petrik, J., Němec, P., Ševčı́ková, S., Minařík, J., Štefániková, Z., et al. (2013) · Genomics · doi:10.1016/j.ygeno.2013.06.007 · Cited by 14
Could we also be regenerative superheroes, like salamanders?
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“programs that induce either G1 cell cycle phase arrest or apoptosis [112, 113], thus pointing to Rb-p19/ARF-p53 as a key network to maintain the post-mitotic state in terminally differentiated mammalian myotubes [109].”
BackgroundSignificance of Inactivated Genes in Leukemia: Pathogenesis and Prognosis.
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“This tumor suppressor functions upstream of retinoblastoma (Rb) gene to control the cell cycle arrest (65).”
BackgroundNSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma
D’Agostino, L., & Giordano, A. (2010) · Oncotarget · doi:10.18632/oncotarget.176 · Cited by 14
“7, 8, 9), there was no significant changes observed between the controls and treated cells for the following proteins which can be involved in apoptosis: p53 levels [31], B23 [33], Bax [34], cytochrome c [35], as well as p14Arf [36] and p21 [37] even though not shown.”
BackgroundInfluentialThe Rb/E2F pathway and Ras activation regulate RecQ helicase gene expression
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An evaluation of palbociclib as a breast cancer treatment option: a current update
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“INK4 family proteins such as the prototypical p16 directly bind CDK4 to inhibit cyclin D-CDK4 activity [14].”
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“22,23 It is suspected that homozygous deletion of CDKN2A/B , which breaks the “brake” of tumor progression brake, nullifies the tumor-suppressive environment created by IDH - mutant astrocytomas.”
Genetics, cellular biology and tumor microenvironment of melanoma
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Knock down of hSNF5/Ini1 causes cell cycle arrest and apoptosis in a p53-dependent manner
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“p14ARF induction generally causes cell-cycle arrest in G1 and G2 phases and apoptosis [139,190,191].”
BackgroundSignal Transduction Involving the Dmp1 Transcription Factor and its Alteration in Human Cancer
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“The activity of p53 is positively regulated by p19Arf (p14ARF in humans) in response to oncogenic stress (Lowe and Sherr, 2003; Sherr, 2001, 2006). p19Arf directly binds to Mdm2, thereby stabilizing and activating p53, whereas p16Ink4a binds to cdk4 to inhibit Rb phosphorylation (for reviews, Kim…”
BackgroundInfluentialThe Rb family connects with the Tp53 family in skin carcinogenesis
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“dependent kinase inhibitors [21,22], which comprise two subclasses: the ink4 family, which binds specifically Cdk4 and 6, and includes p16, p15, p18, and p19 [23], and the cip/kip family, which can bind and”
BackgroundRudenko, H. C., Else, M., Dearden, C. E., Brito‐Babapulle, V., Jones, C., Dexter, T., Fenwick, K., Mackay, A. G., Ashworth, A., Matutes, E., et al. (2008) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190802345902 · Cited by 13
“ARF is involved in tumor suppression in both TP53 dependent and independent pathways [29,30].”
BackgroundWilliams, R. T., & Sherr, C. J. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-69116-9_9 · Cited by 13
“1 Organization and Regulation of the INK4A/ARF Locus The CDKN2A tumor suppressor locus (hereafter INK4A/ARF) encodes two distinct tumor suppressor genes (Lowe and Sherr 2003).”
BackgroundSelf-citationTherapy-Induced Apoptosis in Primary Tumors
McConkey, D. J. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-74039-3_3 · Cited by 13
The biology of cyclins and cyclin-dependent protein kinases: an introduction.
Miele, L. (2004) · Methods in molecular biology · doi:10.1385/1-59259-822-6:003 · Cited by 17
Genetic and epigenetic alterations in lung tumors from bitransgenic Ki‐rasG12C expressing mice
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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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