Cited by 534Cancer-related Molecular PathwaysTelomeres, Telomerase, and SenescenceChromatin Remodeling and Cancer

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The INK4A/ARF locus and its two gene products.

Sharpless, Norman E, DePinho, Ronald A·1999·Current Opinion in Genetics & Development

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Abstract

The INK4A/ARF locus on chromosome 9 is one of the sites mutated most frequently in human cancer. Two genes comprising overlapping reading frames encoding p16(INK4a) and p19(ARF) have been discovered at this locus and, remarkably, both play an important role in regulating cell growth, survival and senescence.

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van Lohuizen, M. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80053-7 · Cited by 78
Regulation of disease‐responsive genes mediated by epigenetic factors: interaction of Arabidopsis–Pseudomonas
De‐la‐Peña, C., RANGEL‐CANO, A., & Álvarez-Venegas, R. (2011) · Molecular Plant Pathology · doi:10.1111/j.1364-3703.2011.00757.x · Cited by 77
Wild-Type p53 Overexpression and Its Correlation With MDM2 and p14ARF Alterations: An Alternative Pathway to Non–Small-Cell Lung Cancer
Wang, Y.-C., Lin, R.-K., Tan, Y. C., Chen, J.-T., Chen, C., & Wang, Y. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2005.03.139 · Cited by 77
Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants
Greenblatt, M. S., Beaudet, J. G., Gump, J., Godin, K. S., Trombley, L. M., Koh, J., & Bond, J. P. (2003) · Oncogene · doi:10.1038/sj.onc.1206101 · Cited by 76
“This function has been attributed to ARF’s first exon, which does not overlap with the p16 coding sequence (Sharpless and Depinho, 1999).”
Background
Polycomb group genes as epigenetic regulators of normal and leukemic hemopoiesis
Lessard, J. A., & Sauvageau, G. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(03)00081-x · Cited by 76
“This connection is of considerable interest because this locus encodes the main regulators of the immortalization/senescence checkpoint in rodent and human primary cells (reviewed in [156]).”
Background
Busulfan Selectively Induces Cellular Senescence but Not Apoptosis in WI38 Fibroblasts via a p53-Independent but Extracellular Signal-Regulated Kinase-p38 Mitogen-Activated Protein Kinase-Dependent Mechanism
Probin, V., Wang, Y., Bai, A., & Zhou, D. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.107771 · Cited by 75
“Two major pathways have been implicated in the induction of senescence (Sharpless and DePinho, 1999; Shay and Wright, 2000; Serrano and Blasco, 2001; Marcotte and Wang, 2002; Campisi, 2005): the p53-p21 pathway triggered by DNA damage or telomere shortening and the p16-retinoblastoma pathway activated by the Ras-Raf-m…”
BackgroundInfluential
Immunolocalization of Human p14ARF to the Granular Component of the Interphase Nucleolus
Lindström, M. S., Klangby, U., Inoue, R., Pisa, P., Wiman, K. G., & Asker, C. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4854 · Cited by 77
Obligate Roles for p16 Ink4a and p19 Arf -p53 in the Suppression of Murine Pancreatic Neoplasia
Bardeesy, N. M., Morgan, J. A., Sinha, M., Signoretti, S., Srivastava, S., Loda, M. F., Merlino, G. T., & DePinho, R. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.635-643.2002 · Cited by 74
“High levels of EGFR signaling may also result in growth-antagonizing effects due to RAS-mediated induction of p19-p53 and p16 (47); hence, loss of these”
BackgroundSelf-citation
Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways
Weber, H. O., Samuel, T., Rauch, P., & Funk, J. O. (2002) · Oncogene · doi:10.1038/sj.onc.1205429 · Cited by 74
“Exon 2 is transcribed in distinct readings frames such that there is no amino acid homology between the two proteins (Chin et al., 1998b; Sharpless and DePinho, 1999). p16Ink4a belongs to the INK4 family of cyclindependent kinase (CDK) inhibitors and inhibits CDK 4 and 6 activities, thus leading to…”
Background
A mutation hotspot at the p14ARF splice site
Harland, M., Taylor, C., Chambers, P. A., Kukalizch, K., Randerson‐Moor, J. A., Gruis, N. A., de Snoo, F. A., ter Huurne, J., Goldstein, A. M., Tucker, M. A., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1208678 · Cited by 73
“This interaction prevents MDM2 from promoting the destruction of the p53 tumor suppressor protein, stabilizing p53 and resulting in cell cycle arrest at the G1/G2 phase (Sharpless and DePinho, 1999; Sherr, 2001).”
Background
Accumulating Active p53 in the Nucleus by Inhibition of Nuclear Export: A Novel Strategy to Promote the p53 Tumor Suppressor Function
Laı́n, S., Xirodimas, D. P., & Lane, D. P. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4672 · Cited by 72
The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans
Carrasco, D. R., Fenton, T. R., Sukhdeo, K., Protopopova, M., Enos, M., You, M. J., Divicio, D., Nogueira, C., Stommel, J. M., Pinkus, G. S., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.028 · Cited by 69
“…tumor suppressors, p16INK4A and p14ARF (p19ARF in mice) that function as regulators of the pRB and p53 pathways, respectively (Quelle et al., 1995; Sharpless and DePinho, 1999). p16INK4A and other members of the INK4A S I G N I F I C A N C E HS in humans is a raremalignancy that is typically very…”
BackgroundInfluentialSelf-citation
Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model
Sethi, N. S., Kikuchi, O., Duronio, G. N., Stachler, M. D., McFarland, J. M., Ferrer-Luna, R., Zhang, Y., Bao, C., Bronson, R. T., Patil, D. T., et al. (2020) · Nature Genetics · doi:10.1038/s41588-019-0574-9 · Cited by 69
Dysregulated Expression of Stem Cell Factor Bmi1 in Precancerous Lesions of the Gastrointestinal Tract
Tateishi, K., Ohta, M., Kanai, F., Guleng, B., Tanaka, Y., Asaoka, Y., Tada, M., Seto, M., Jazag, A., Lianjie, L., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0449 · Cited by 67
Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer
Talati, P. G., Gu, L., Ellsworth, E., Girondo, M. A., Trerotola, M., Hoang, D. T., Leiby, B. E., Dagvadorj, A., McCue, P. A., Lallas, C. D., et al. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.04.026 · Cited by 68
ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress
Pauklin, S., Kristjuhan, A., Maimets, T., & Jaks, V. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.06.097 · Cited by 69
Understanding genomics and the immune environment of penile cancer to improve therapy
Aydın, A. M., Chahoud, J., Adashek, J. J., Azizi, M., Magliocco, A. M., Ross, J. S., Necchi, A., & Spiess, P. E. (2020) · Nature Reviews Urology · doi:10.1038/s41585-020-0359-z · Cited by 66
Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma.
Thompson, P. M., Maris, J. M., Hogarty, M. D., Seeger, R. C., Reynolds, C. P., Brodeur, G. M., & White, P. S. (2001) · PubMed · Cited by 65
Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases
Shreeya, T., Ansari, M. S., Kumar, P., Saifi, M., Shati, A. A., Alfaifi, M. Y., & Elbehairi, S. E. I. (2024) · Frontiers in Aging · doi:10.3389/fragi.2023.1292053 · Cited by 72
“It plays a pivotal role in the process of DDR, causes cell cycle arrest thereby promoting cellular senescence (Sharpless and Depinho, 1999; Sherr and Hughes, 2001).”
Background
From the Rarest to the Most Common: Insights from Progeroid Syndromes into Skin Cancer and Aging
Capell, B. C., Tlougan, B. E., & Orlow, S. J. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2009.103 · Cited by 66
“, 2009), it is not surprising that disrupting either the p53 or p16 pathways can lead to melanoma and non-melanoma skin cancers (Sharpless and DePinho, 1999; Ouhtit et al., 2000a, b; Recio et al., 2002).”
Background
Epigenetic regulation of p14 and p16 expression in cutaneous and uveal melanoma
Venza, M., Visalli, M., Biondo, C., Lentini, M., Catalano, T., Teti, D. V., & Venza, I. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.12.004 · Cited by 64
“As p14 and p16 are the main cell cycle regulatory genes [32] and their knockdown plays an important role in tumorigenic transformation [33], we have investigated whether the ectopic expression of these genes might affect melanoma cell proliferation, migration and invasion.”
Background
Establishment and Characterization of a Continuous Human Chondrosarcoma Cell Line, ch-2879: Comparative Histologic and Genetic Studies with Its Tumor of Origin
Gil‐Benso, R., López‐Ginés, C., López‐Guerrero, J. A., Cardá, C., Callaghan, R. C., Navarro, S., Ferrer-Lozano, J., Pellı́n, A., & Llombart‐Bosch, A. (2003) · Laboratory Investigation · doi:10.1097/01.lab.0000073131.34648.ea · Cited by 64
“p14 protein is a potent regulator of the cell cycle, acting upstream in the p53 pathway by binding to MDM2 and preventing p53 degradation, thus permitting p53-induced apoptosis or growth arrest (Lundberg and Weinberg, 1999; Sharpless and DePinho, 1999).”
Background
Mitochondrial HEP27 Is a c-Myb Target Gene That Inhibits Mdm2 and Stabilizes p53
Deisenroth, C., Thorner, A. R., Enomoto, T., Perou, C. M., & Zhang, Y. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01284-09 · Cited by 64
“A number of cellular proteins, including Myc, Ras, and E2F1, when overexpressed or constitutively active, can promote p53 stabilization via the inhibition of Mdm2 by the tumor suppressor p19Arf (47).”
Background
Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma
Laud, K., Marian, C., Avril, M.-F., Barrois, M., Chompret, A., Goldstein, A. M., Tucker, M. A., Clark, P. A., Peters, G., Chaudru, V., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.033498 · Cited by 64
“Both p16 and p15 are able to cause a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein (Rb), while p14 can arrest cells in both G1 and G2/M phases via its ability to inhibit MDM2-mediated destruction of the p53 tumor suppressor (reviewed in ref [2]).”
Background
CARF Is a Novel Protein That Cooperates with Mouse p19 (Human p14 ) in Activating p53
Hasan, M. K., Yaguchi, T., Sugihara, T., Kumar, P. K. R., Taira, K., Reddel, R. R., Kaul, S. C., & Wadhwa, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204177200 · Cited by 65
Absence of p16 INK4a and truncation of ARF tumor suppressors in chickens
Kim, S.-H., Mitchell, M., Fujii, H., Llanos, S., & Peters, G. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0135557100 · Cited by 63
Role of Apaf‐1, a key regulator of apoptosis, in melanoma progression and chemoresistance
Campioni, M., Santini, D., Tonini, G., Murace, R., Dragonetti, E., Spugnini, E. P., & Baldi, A. (2005) · Experimental Dermatology · doi:10.1111/j.1600-0625.2005.00360.x · Cited by 64
“In fact, the first identified and best-known locus associated with melanoma susceptibility in humans is found on chromosome 9p21 and is known variously as cyclin-dependent kinase inhibitor 2A (CDK2A), multiple tumor suppressor 1, or INK4-ARF (57,58).”
Background
p16(INK4a) and p53 deficiency cooperate in tumorigenesis.
Sharpless, N. E., Alson, S., Chan, S., Silver, D. P., Castrillón, D. H., & DePinho, R. A. (2002) · PubMed · Cited by 63
Self-citation
Genetically engineered mouse models of prostate cancer
Parisotto, M., & METZGER, D. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.02.005 · Cited by 68
“Inactivation of INK4a/ARF is known to be associated with a variety of human cancers (Burri et al., 2001; Sharpless and DePinho, 1999).”
Background
Association Between INK4a-ARF and p53 Mutations in Skin Carcinomas of Xeroderma Pigmentosum Patients
Soufir, N. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.22.1841 · Cited by 62
Tracking the Shift to ‘Postgenomics’
Stotz, K. C., Bostanci, A., & Griffiths, P. E. (2006) · Public Health Genomics · doi:10.1159/000092656 · Cited by 61
“put it, annotation always involves an ‘executive decision about the relevancy, accuracy, and quality of the evidence, and by definition exposes the curator’s point of view’. Practitioners thus stress that annotation is an open-ended process that depends on future evidence and subjective judgments. However, the argumen…”
Common and reversible regulation of wild-type p53 function and of ribosomal biogenesis by protein kinases in human cells
David-Pfeuty, T., Nouvian-Dooghe, Y., Sirri, V., Roussel, P., & Hernandez-Verdun, D. (2001) · Oncogene · doi:10.1038/sj.onc.1204741 · Cited by 62
“…only recently that wt p53 could also be activated and initiate these pathways in response to other types of signals, like hypoxia (Graeber et al., 1996), oncogenes (via the Arf protein; for review see Sharpless and DePinho, 1999) and depletion of ribonucleotide triphosphates (Linke et al., 1996).”
Background
Infectious delivery of the 132 kb CDKN2A/CDKN2B genomic DNA region results in correctly spliced gene expression and growth suppression in glioma cells
Inoue, R., Moghaddam, K. A., Ranasinghe, M., Saeki, Y., Chiocca, E. A., & Wade‐Martins, R. (2004) · Gene Therapy · doi:10.1038/sj.gt.3302284 · Cited by 61
With ‘Genes’ Like That, Who Needs an Environment? Postgenomics's Argument for the ‘Ontogeny of Information’
Stotz, K. C. (2006) · Philosophy of Science · doi:10.1086/518748 · Cited by 63
MiR-433 and miR-127 Arise from Independent Overlapping Primary Transcripts Encoded by the miR-433-127 Locus
Song, G., & Wang, L. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003574 · Cited by 60
Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells
Zhang, X., Li, J., Sejas, D. P., & Pang, Q. (2005) · Blood · doi:10.1182/blood-2004-08-3033 · Cited by 60
AIMP3 Haploinsufficiency Disrupts Oncogene-Induced p53 Activation and Genomic Stability
Park, B.-J., Oh, Y. S., Park, S., Choi, S. J., Rudolph, C., Schlegelberger, B., & Kim, S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3740 · Cited by 58
“Because p14/ARF has been suggested as the mediator in the oncogene-mediated p53 activation through the suppression of MDM2 (16), we determined the engagement of p14/ARF in the Rasdependent induction of p53 by testing whether Ras as well as growth factors could still activate p53 in a p14-deficient human osteosarcoma c…”
Combined modulation of polycomb and trithorax genes rejuvenates β cell replication
Zhou, J. X., Dhawan, S., Fu, H., Snyder, E., Bottino, R., Kundu, S., Kim, S. K., & Bhushan, A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69468 · Cited by 59
“Further evidence for a role for Ink4a-mediated control of β cell expansion was provided by genome-wide association studies linking the Ink4a/Arf locus to insulin insufficiency and risk of type 2 diabetes in humans (16, 17).”
Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia
Kresty, L. A., Mallery, S. R., Knobloch, T. J., Li, J., Lloyd, M., Casto, B. C., & Weghorst, C. M. (2008) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-08-0574 · Cited by 58
“Allelic loss at 9p has been associated with histologic progression to cancer, cancer recurrence, and responsiveness to treatment (3-34).”
Background
DNA methylation, nuclear structure, gene expression and cancer
Heinrich, L., & Cardoso, M. C. (2000) · Journal of Cellular Biochemistry · doi:10.1002/1097-4644(2000)79:35+ · Cited by 97
9p21 locus analysis in high‐risk gastrointestinal stromal tumors characterized for c‐kit and platelet‐derived growth factor receptor α gene alterations
Perrone, F., Tamborini, E., Dagrada, G. P., Colombo, F., Bonadiman, L., Albertini, V., Lagonigro, M. S., Gabanti, E., Caramuta, S., Greco, A., et al. (2005) · Cancer · doi:10.1002/cncr.21113 · Cited by 58
“Homozygous p16INK4a deletion, which always is coupled with p14ARF gene loss, seems to be the most common 9p21 inactivation mechanism in GISTs.”
ResultInfluential
The yin and yang of the Cdkn2a locus in senescence and aging
Baker, D. J., Jin, F., & van Deursen, J. M. (2008) · Cell Cycle · doi:10.4161/cc.7.18.6687 · Cited by 56
MEK-ERK Signaling Controls Hdm2 Oncoprotein Expression by Regulating hdm2 mRNA Export to the Cytoplasm
Phelps, M., Phillips, A., Darley, M., & Blaydes, J. P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412334200 · Cited by 57

Authors: Sharpless, N. E., & DePinho, R. A.
Affiliations: Dana-Farber Cancer Institute (US)
Corresponding author: DePinho, Ronald A
ORCID: Sharpless, Norman E
DePinho, Ronald A
Venue: Current Opinion in Genetics & Development
Publisher: Elsevier BV
Published: 1999-02
Volume: 9
Issue: 1
Pages: 22-30
ISSN: 0959-437X (ISSN-L)
DOI: 10.1016/s0959-437x(99)80004-5
OpenAlex: W1991595805
Cited by: 533
References: 92
Citations by year: 2026: 4 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 15 · 2020: 8 · 2019: 9 · 2018: 11 · 2017: 4 · 2016: 12 · 2015: 9 · 2014: 12 · 2013: 21 · 2012: 15
FWCI: 5.41
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Current Opinion in Genetics & Development (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hd028317-05, 7r01ey011267-04)
National Eye Institute (R01EY11267)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD28317)
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 › Chromatin Remodeling and Cancer
Keywords: INK4a/ARF locus, p16INK4a, p19ARF, chromosome 9, tumor suppressor, cell cycle regulation, cellular senescence, cell growth, cell survival, cancer mutations
MeSH terms: Amino Acid Sequence, Humans, Molecular Sequence Data, Mutation, Neoplasms, Proteins, Genes, Tumor Suppressor, Sequence Homology, Amino Acid, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Tumor Suppressor Protein p14ARF

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The INK4A/ARF locus and its two gene products.

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