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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Mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk.
“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]
p16INK4a is poorly induced in senescent BJ fibroblasts.
“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
p16INK4a appears dispensable for senescence in MEFs.
“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
p16 is induced by a variety of stressful stimuli, including overexpression of oncogenes such as RAS and suboptimal culture conditions.
“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
The p16-Arf locus encodes 2 tumor suppressors, p16 and Arf.
“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]
p16 functions as a cyclin-dependent kinase (CDK) 4/6 inhibitor.
“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]
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.
“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]
The biological action of Arf relies on the p53 pathway because Arf can directly bind to MDM2 and cause accumulation of p53 by segregating MDM2 from p53 and by inhibiting MDM2's E3 ubiquitin protein ligase activity for p53.
“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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“Moreover, c-Myc can enhance p53 expression through p19Arf (31).”
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“allow cells to ignore certain senescence-inducing signals and greatly increase cancer susceptibility [6, 7].”
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“The p19 protein stabilizes the tumor suppressor p53 protein by interfering with Mdm2-mediated p53 degradation, thereby allowing accumulation of p53 transcription factor and stimulating transcription of the CDKI p21 gene (39).”
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“…al., 2005; Molofsky et al., 2005). p16 Ink4a is a cyclin-dependent kinase inhibitor that promotes Rb activation, slowing cell-cycle progression or inducing cellular senescence (Lowe and Sherr, 2003). p19 Arf promotes p53 activity, also slowing cell-cycle progression or inducing cellular senescence.”
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Divorcing ARF and p53: an unsettled case
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Self-citationtp53 mutant zebrafish develop malignant peripheral nerve sheath tumors
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Inactivation of the p53 pathway in retinoblastoma
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“Rb activation, changes in p21 cip1 expression affect the levels of p16 Ink4a that are required to inhibit proliferation (Lowe and Sherr 2003).”
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“…1994; Wagner et al., 1994; Zindy et al., 1998) and suppress proliferation (Finch et al., 2006). p19ARF may also exert p53-independent tumor-suppressive functions (Lowe and Sherr, 2003), in part mediated by direct binding and functional inactivation of Myc (Datta et al., 2004; Qi et al., 2004).”
BackgroundNucleolus, Ribosomes, and Cancer
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“The Arf gene is induced by a series of stress signals such as hyperproliferative signals emanating from oncogenic Ras and overexpressed Myc and may be mutated or silenced in tumor cells.(50,51) p14Arf helps the stabilization of p53 by binding to Hdm2, the factor responsible for p53 degradation.”
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BackgroundInfluentialRole of the proto-oncogene Pokemon in cellular transformation and ARF repression
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“…pathways, inactivation of retinoblastoma (RB) proteins by E1A and inhibition of p53 by E1B, reflect the inactivation of these two critical transcription regulatory proteins or the pathways in which they operate in nearly all human cancer cells (Sherr and McCormick, 2002; Lowe and Sherr, 2003).”
BackgroundOncogene-Induced Cell Senescence — Halting on the Road to Cancer
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CHD5 Is a Tumor Suppressor at Human 1p36
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“In exploring the mechanism whereby Chd5 modulates p53, we discovered that p19Arf, an upstream inducer of p53 that is activated by oncogene-induced pathways (Lowe and Sherr, 2003), is severely compromised by Chd5 deficiency.”
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Total body irradiation selectively induces murine hematopoietic stem cell senescence.
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Role of genomic instability and p53 in AID-induced c-myc–Igh translocations
Ramiro, A. R., Janković, M., Callén, E., Difilippantonio, S., Chen, H.-T., McBride, K. M., Eisenreich, T., Chen, J., Dickins, R. A., Lowe, S. W., et al. (2006) · Nature · doi:10.1038/nature04495 · Cited by 346 · see citing works
Self-citationEmerging roles of p53 and other tumour-suppressor genes in immune regulation
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“…key sensors and transducers such as p53 to the activation of downstream effector responses that control cellular proliferation in order to avoid propagation of damaged cells or the progression of initiated tumors (ElDeiry, 1998; Vousden and Lu, 2002; Lowe and Sherr, 2003; Sax and El-Deiry, 2003).”
Backgroundp53 Acetylation: Regulation and Consequences
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“Acetylation of p53-K120 occurs after exposure to many different types of DNA damage [77,78] as well as expression of the Alternative Reading Frame (ARF) tumor suppressor [79], a major p53 activator that mediates the oncogene checkpoint [23].”
BackgroundHematopoietic Stem Cell Injury Induced by Ionizing Radiation
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“Once SAHF are formed after the engagement of the p16-Rb pathway, the cells become permanently growth arrested and senescent.”
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“Ink4a and Arf are important players in the retinoblastoma (pRB) and p53 pathways, respectively, and their activation results in growth arrest, senescence, or apoptosis (for review, see Sharpless and DePinho 1999; Lowe and Sherr 2003).”
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What has senescence got to do with cancer?
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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 304 · see citing works
“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 · see citing works
“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
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Nucleophosmin (B23) Targets ARF to Nucleoli and Inhibits Its Function
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“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
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“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…”
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Toward a Molecular Classification of Melanoma
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An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors
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“…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).”
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“(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
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“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
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A Short Mitochondrial Form of p19ARF Induces Autophagy and Caspase-Independent Cell Death
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“, 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
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“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 · see citing works
“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 · see citing works
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“(Lowe and Sherr, 2003; Serrano et al., 1995, 1996).”
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“p16Ink4a binds to cyclin-dependent kinases (CDK) 4/6 to prevent their interaction with cyclin D and thus, inhibits CDK4/6 activity [75].”
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Mechanisms controlling cell cycle exit upon terminal differentiation
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Reactive oxygen species and hematopoietic stem cell senescence
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“HSCs from Bmi1−/− mice express increased levels of p16 and Arf [27, 57, 58].”
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“To further substantiate this observation, we used two independent markers of senescence, p16 and p19 (26).”
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Oncogenic activity of Cdc6 through repression of the INK4/ARF locus
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“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).”
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Regulating the p53 system through ubiquitination
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“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
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“Similarly, mutations that activate several oncogenes (Ras and myc) increase ARF levels and activate p53 (9).”
Background
- 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
- Health Sciences › Medicine › Physiology › 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 ›
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