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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“This blockade leads to decreased phosphorylation of Rb protein with subsequent arrest in the G1 phase of the cell cycle (Sharpless and DePinho, 1999).”
Background
Frequency of Genetic and Epigenetic Alterations of p14ARF and p16INK4A in Head and Neck Cancer in a Hungarian Population
Kis, A., Tatár, T. Z., Gáll, T., Boda, R., Tar, I., Major, T., Redl, P., Gergely, L., & Szarka, K. (2014) · Pathology & Oncology Research · doi:10.1007/s12253-014-9775-9 · Cited by 12
“sharing a common second [14] and possibly also a third exon [15, 16].”
Background
Preparation and Immortalization of Primary Murine Cells
Sharpless, N. E. (2006) · Elsevier eBooks · doi:10.1016/b978-012164730-8/50029-0 · Cited by 12
Self-citation
Structural Consequences of Tumor-Derived Mutations in p16INK4a Probed by Limited Proteolysis
Zhang, B., & Peng, Z.-Y. (2002) · Biochemistry · doi:10.1021/bi0117100 · Cited by 12
Melanoma — Epidemiology, Genetics and Risk Factors
John, A., Jarrett, S. G., Marsch, A. F., Lagrew, J. P., & Cleary, L. C. (2013) · InTech eBooks · doi:10.5772/55172 · Cited by 16
An Immunohistochemical and Ultrastructural Study of Pancreatic Microcystic Serous Cyst Adenoma with Special Reference to Tumor-Associated Microvasculature and Vascular Endothelial Growth Factor in Tumor Cells
Yamazaki, K., & Eyden, B. P. (2006) · Ultrastructural Pathology · doi:10.1080/01913120500407960 · Cited by 11
The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer
Weng, C., Lin, Y., & Cheng, K. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091369 · Cited by 12
Régulation de p16INK4a, senescence et oncogenèse
Chien, W. W., & Ffrench, M. (2006) · médecine/sciences · doi:10.1051/medsci/20062210865 · Cited by 11
“Le locus INK4a/ARF humain, situé sur le chromosome 9 en 9p21, comporte deux gènes, INK4a et ARF, qui expriment respectivement les transcrits α et β : ces transcrits codent pour les protéines p16INK4a et p14ARF (p19ARF chez la souris), distinctes sur les plans structural et fonctionnel [10].”
Background
Genomic rearrangements of the CDKN2A locus are infrequent in Italian malignant melanoma families without evidence of CDKN2A/CDK4 point mutations
Vignoli, M., Scaini, M. C., Ghiorzo, P., Sestini, R., Bruno, W., Menin, C., Gensini, F., Piazzini, M., Testori, A., Manoukian, S., et al. (2008) · Melanoma Research · doi:10.1097/cmr.0b013e328319412f · Cited by 11
Control of virus infection by tumour suppressors
Muñoz‐Fontela, C., García, M. Á., Collado, M., Marcos-Villar, L., Gallego, P. P. F., Estéban, M., & Rivas, C. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm048 · Cited by 13
“of the most frequently mutated genes in cancer [49,50].”
Background
The shady side of sunlight current understanding of the mechanisms underlying UV-induction of skin cancers
Trappey, A. (2009) · Frontiers in Bioscience-Scholar · doi:10.2741/s42 · Cited by 10
“CDKN2A (INK4a/ARF) locus encodes for two distinct tumor suppressor proteins: p16INKa, the inhibitor of kinase 4A, and p14ARF (44-47).”
Background
Immortalization of primary marmoset skin fibroblasts by CRISPR-Cas9-mediated gene targeting
Jeong, Y.-J., Cho, J., Kwak, J., Sung, Y. H., & Kang, B. (2022) · Animal Cells and Systems · doi:10.1080/19768354.2022.2151509 · Cited by 10
Tumor suppressor p16INK4A/Cdkn2a alterations in 7, 12‐dimethylbenz(a)anthracene (DMBA)‐induced hamster cheek pouch tumors
Li, J., Warner, B. M., Casto, B. C., Knobloch, T. J., & Weghorst, C. M. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20424 · Cited by 10
“While aberrant 50-CpG methylation in p16 exon 1a should not affect p16/Arf exon 1b, deletions and point mutations in p16 exon 2 may also bring about alterations in p16/Arf, which consequently down-regulates another tumor suppressive pathway, the CDKN2A-ARF/P53/MDM2 pathway [30,31].”
Background
Modulation of p53 expression and its role in the conversion to a fully immortalized chicken embryo fibroblast line
Christman, S. A., Kong, B. C., Landry, M. M., Kim, H., & Foster, D. N. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.10.066 · Cited by 10
“stream of p53 by binding to MDM-2, preventing it from degrading p53 [24,25].”
Background
Large scale genotyping study for asthma in the Japanese population
Imada, Y., Fujimoto, M., Hirata, K., Hirota, T., Suzuki, Y., Saito, H., Matsumoto, K., Akazawa, A., Katsunuma, T., Yoshihara, S., et al. (2009) · BMC Research Notes · doi:10.1186/1756-0500-2-54 · Cited by 10
“p19ARF proteins regulate p53 pathways, and the disruption of these proteins results in aberrant cell cycle regulation and perturbation of apoptotic response [20].”
Background
Transfer of p14ARF gene in drug-resistant human breast cancer MCF-7/Adr cells inhibits proliferation and reduces doxorubicin resistance
Guo-chang, F. (2000) · Cancer Letters · doi:10.1016/s0304-3835(00)00524-3 · Cited by 10
The INK4a/ARF Locus and Human Cancer
Enders, G. H. (2003) · Humana Press eBooks · doi:10.1385/1-59259-328-3:197 · Cited by 10
Aging of Fibroblasts
Kletsas, D. (2003) · Springer eBooks · doi:10.1007/978-94-017-0669-8_3 · Cited by 9
Rules for Making Human Tumor Cells
(2003) · New England Journal of Medicine · doi:10.1056/nejm200302133480727 · Cited by 9
p16INK4a/Ki67 Dual-Staining Immunocytochemistry to Refer Women Infected by High-Risk Human Papillomavirus for Colposcopy
Doeberitz, M. V. K. (2025) · Acta Cytologica · doi:10.1159/000542504 · Cited by 8
“p16 INK4a is a tumor suppressor protein encoded by the CDKN2A gene located on chromosome 9p21 [25].”
A novel CDKN 2A variant (p16L117P) in a patient with familial and multiple primary melanomas
Li, C., Liu, T., Liu, B., Trapero, R. H., Facelli, J. C., & Grossman, D. (2019) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12787 · Cited by 8
The association of a genetic variant in CDKN2A/B gene and the risk of colorectal cancer
Rahmani, F., Avan, A., Amerizadeh, F., Ferns, G. A., Talebian, S., & Shahidsales, S. (2020) · EXCLI journal · doi:10.17179/excli2020-2051 · Cited by 9
“The p15INK4B and 16INK4A tumor suppressor proteins induce cell cycle arrest by downregulating cyclin-dependent kinase 4 and 6 (CDK4, 6) while the p14ARF protein promotes apoptosis and cell cycle arrest by promoting mdm2 - p53 signaling pathway (Krimpenfort et al., 2019; Sharpless and DePinho, 1999).”
Background
Chemotherapy Drug Induced Discoordination of Mitochondrial Life Cycle Detected by Cardiolipin Fluctuation
Chao, Y.-J., Chan, J.-F., & Hsu, Y. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162457 · Cited by 8
“Inhibition of the CDK (s) by CDK interacting protein/kinase inhibitory protein family (cip/kip) [7] and the inhibitor of kinase 4/alternative reading frame family (INK4a/ARF) [8,9] would trigger cell cycle arrest.”
Background
Expression and tissue distribution of human X-linked armadillo repeat containing-6
Kusama, Y., Takayanagi, S., Tategu, M., & Yoshida, K. (2010) · Experimental and Therapeutic Medicine · doi:10.3892/etm_00000062 · Cited by 8
Aberrant Methylation in Promoters of GSTP1, p16, p14, and RASSF1A Genes in Smokers of North India
Deep, J. S., Sidhu, S., Chandel, A., Thapliyal, S., & Garg, C. (2012) · ISRN Pulmonology · doi:10.5402/2012/247631 · Cited by 8
The INK4A/Arf Network — Cell Cycle Checkpoint or Emergency Brake?
del Arroyo, A. G., & Peters, G. G. (2005) · Advances in experimental medicine and biology · doi:10.1007/1-4020-3764-3_8 · Cited by 8
“For more detailed information, the reader can refer to a number of previous reviews (Drayton and Peters, 2002; Ruas and Peters, 1998; Sharpless and DePinho, 1999; Sherr, 2001).”
p16 Ink4a Interferes with Abelson Virus Transformation by Enhancing Apoptosis
Sachs, Z., Sharpless, N. E., DePinho, R. A., & Rosenberg, N. E. (2004) · Journal of Virology · doi:10.1128/jvi.78.7.3304-3311.2004 · Cited by 8
“Mutations or epigenetic changes affecting the Ink4a/Arf locus occur frequently in human tumors, and while some changes affect both products, others affect p16 or p19 alone (35, 44).”
BackgroundInfluentialSelf-citation
Quantitative assessment of aberrant P16INK4a methylation in ovarian cancer: a meta-analysis based on literature and TCGA datasets
Ruan, J., Xu, P., Fan, W., Deng, Q., & Yu, M. (2018) · Cancer Management and Research · doi:10.2147/cmar.s170818 · Cited by 7
“P16 (also known as CDKN2A), a classical TSG, is located on chromosome 9p21 and plays an important role in cell cycle regulation by decelerating cells progression from G1 to S phase.(11,12) It has become clear that the expression of P16 is reduced by DNA methylation.”
Novel Biomarkers and Druggable Targets in Advanced Melanoma
Ferrucci, P. F., & Cocorocchio, E. (2021) · Cancers · doi:10.3390/cancers14010081 · Cited by 7
“Cyclin-dependent kinase-2a and 2b (CDKN2a-CDKN2b) are located in the INK4 locus on chromosome 9p21 and encode respectively for tumor suppressor p16 and p15, which act as CDK inhibitors, being associated with a predisposition to melanoma [38].”
Background
Tumor suppressive pathways in the control of neurogenesis
Bartesaghi, S., & Salomoni, P. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1063-9 · Cited by 8
“As discussed above, p16 directly inhibits the cyclin D1 and cyclin-dependent kinase 4/6 (Cdk4/6) complex, thus leading to Rb activation and inhibition of G1/S progression [215].”
Background
Tumor suppressor ARF
Través, P. G., Luque, A., & Hortelano, S. (2012) · OncoImmunology · doi:10.4161/onci.19948 · Cited by 7
Up-regulated expression of E2F2 is necessary for p16INK4a-induced cartilage injury
Bao, X., & Hu, X. (2018) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-018-2253-x · Cited by 8
EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells
Miyanaga, A., Matsumoto, M., Beck, J. A., Horikawa, I., Oike, T., Okayama, H., Tanaka, H., Burkett, S. S., Robles, A. I., Ma, K., et al. (2021) · BMC Cancer · doi:10.1186/s12885-021-07905-6 · Cited by 7
Methylation Status of P16Ink4a in Human Papillomavirus-Associated Cancer of Oral Cavity and Oropharynx in Northeastern Thailand
Swangphon, P., Pientong, C., Burassakarn, A., Vatanasapt, P., Kleebkaow, P., Patarapadungkit, N., Treebupachatsakul, T., Promthet, S. S., Kongyingyoes, B., & Ekalaksananan, T. (2017) · Europe PMC (PubMed Central) · doi:10.22034/apjcp.2017.18.3.699 · Cited by 7
“Increase of transcriptional factors or host oncoproteins can up-regulate expression of this gene (Sharpless and DePinho, 1999).”
Background
Role of Cdkn2a in the Emery–Dreifuss Muscular Dystrophy Cardiac Phenotype
Pegoli, G., Milan, M., Manti, P. G., Bianchi, A., Lucini, F., Santarelli, P., Bearzi, C., Rizzi, R., & Lanzuolo, C. (2021) · Biomolecules · doi:10.3390/biom11040538 · Cited by 6

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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