The INK4A/ARF locus and its two gene products.
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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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 [11]
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 [11]
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 [11]
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Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., et al. (2001) · Genes & Development · doi:10.1101/gad.886901 · Cited by 716 · see citing works
Patton, E. E., Widlund, H. R., Kutok, J. L., Kopani, K. R., Amatruda, J. F., Murphey, R. D., Berghmans, S., Mayhall, E. A., Traver, D. J., Fletcher, C. D. �., et al. (2005) · Current Biology · doi:10.1016/j.cub.2005.01.031 · Cited by 656 · see citing works
Sherr, C. J., & Weber, J. D. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00038-6 · Cited by 654 · see citing works
Chronic myeloid leukaemia as a model of disease evolution in human cancer
Melo, J. V., & Barnes, D. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2147 · Cited by 616 · see citing works
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice
Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A., & Berns, A. (2001) · Nature · doi:10.1038/35092584 · Cited by 568 · see citing works
“Although most mutations at the CDKN2A locus found in human tumours result in disruption of both the ARF and INK4A transcripts, the presence of point mutations and small deletions that specifically affect p16 INK4a strongly implicate p16 INK4a as a tumour suppresso”
BackgroundUV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer
de Gruijl, F. R., van Kranen, H. J., & Mullenders, L. H. F. (2001) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/s1011-1344(01)00199-3 · Cited by 546 · see citing works
'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
García‐Cao, I., García‐Cao, M., Martín‐Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J., Blasco, M. A., & Serrano, M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf595 · Cited by 529 · see citing works
Cancer and ageing: rival demons?
Campisi, J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1073 · Cited by 512 · see citing works
p16(MTS-1/CDKN2/INK4a) in Cancer Progression
Rocco, J. W., & Sidransky, D. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5149 · Cited by 464 · see citing works
“In a recent reanalysis of 714 primary tumors and cell lines in which the status of p14, p16, and p53 could be reasonably inferred, the authors concluded that the role for p14 in human malignancy appeared to be minor [91].”
BackgroundResultInfluentialNucleolus, Ribosomes, and Cancer
Montanaro, L., Treré, D., & Derenzini, M. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070752 · Cited by 456 · see citing works
“The activity of p53 may also be influenced by changes in the expression of p14Arf, the tumor suppressor protein encoded by the Arf gene located in the Ink4a-Arf locus.(49) The Arf gene is induced by a series of stress signals such as hyperproliferative signals emanating from oncogenic Ras and overexpressed Myc and may…”
BackgroundINK4a/ARF: A multifunctional tumor suppressor locus
Sharpless, N. E. (2005) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2004.08.021 · Cited by 442 · see citing works
Self-citationBmi1, stem cells, and senescence regulation
Park, I.-K., Morrison, S. J., & Clarke, M. F. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420800 · Cited by 495 · see citing works
Pancreatic cancer biology and genetics from an evolutionary perspective
Makohon-Moore, A. P., & Iacobuzio–Donahue, C. A. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.66 · Cited by 430 · see citing works
Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
Baker, D. J., Perez-Terzic, C., Jin, F., Pitel, K. S., Niederländer, N. J., Jeganathan, K., Yamada, S., Reyes, S., Rowe, L., Hiddinga, H. J., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1744 · Cited by 408 · see citing works
“The Cdkn2a locus encodes two separate tumour suppressors, p16 Ink4a , a cyclin-dependent kinase (Cdk) inhibitor that can block G 1 –S progression when present above a certain level, and p19 Arf , a positive regulator of the transcription factor p53 that integrates and responds to a wide variety of cellular stresse”
The power and the promise of oncogene-induced senescence markers
Collado, M., & Serrano, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1884 · Cited by 404 · see citing works
“These two pathways are thought to be crucial for tumour suppression and are often mutated in tumour”
BackgroundReactive Oxygen Species in Normal and Tumor Stem Cells
Zhou, D., Shao, L., & Spitz, D. R. (2014) · Advances in cancer research · doi:10.1016/b978-0-12-420117-0.00001-3 · Cited by 400 · see citing works
“…retinoblastoma protein (Rb) hypophosphorylation and suppresses the expression of E2F-dependent genes, resulting in restriction of G1/S cell cycle progression and formation of senescence-associated heterochromatic foci (SAHF) (Lowe & Sherr, 2003; Narita et al., 2003; Sharpless & DePinho, 1999).”
BackgroundNUMB controls p53 tumour suppressor activity
Colaluca, I. N., Tosoni, D., Nuciforo, P., Senic-Matuglia, F., Galimberti, V., Viale, G., Pece, S., & Di Fiore, P. P. (2008) · Nature · doi:10.1038/nature06412 · Cited by 385 · see citing works
Cell cycle checkpoints and their inactivation in human cancer
Molinari, M. (2000) · Cell Proliferation · doi:10.1046/j.1365-2184.2000.00191.x · Cited by 389 · see citing works
“A more accurate mapping of the INK4a locus has shown that it also encodes another protein, called p19ARF, which has a role in regulating p53 stability and which is frequently found to be mutated in cancer (Roussel 1999; Sharpless & DePinho 1999).”
BackgroundAlterations of the Notch pathway in lung cancer
Westhoff, B., Colaluca, I. N., D’Ario, G., Donzelli, M., Tosoni, D., Volorio, S., Pelosi, G., Spaggiari, L., Mazzarol, G., Viale, G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907781106 · Cited by 388 · see citing works
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381 · see citing works
“Similarly, methylation at the CDKN2A ( INK4a/ARF ) locus can epigenetically silence the expression of the p14ARF protein, and block the ability of activated oncogenes to stabilize the p53 response”
BackgroundDAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation
Raveh, T., Droguett, G., Horwitz, M. S., DePinho, R. A., & Kimchi, A. (2001) · Nature Cell Biology · doi:10.1038/35050500 · Cited by 361 · see citing works
“Among the various mechanisms that activate p53, a role for p19 ARF has been established in which it stabilizes p53 by binding to Mdm2 and preventing p53 degradatio”
BackgroundSelf-citationTotal body irradiation selectively induces murine hematopoietic stem cell senescence.
Wang, Y., Schulte, B. A., LaRue, A. C., Ogawa, M., & Zhou, D. (2006) · Blood · doi:10.1182/blood-2005-04-1418 · Cited by 351 · see citing works
Naive T Cell Maintenance and Function in Human Aging
Goronzy, J. J., Fang, F., Cavanagh, M., Qi, Q., & Weyand, C. M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500046 · Cited by 348 · see citing works
“The INK4A/ARF locus comprises overlapping reading frames of two genes, p16 and p19, that play important roles as cell cycle inhibitors in regulating cell growth and senescence and are mutated in various forms of cancer (74, 75).”
BackgroundPolycomb CBX7 has a unifying role in cellular lifespan.
Gil, J., Bernard, D., Martínez, D., & Beach, D. (2004) · Nature Cell Biology · doi:10.1038/ncb1077 · Cited by 341 · see citing works
“Both p16 Ink4a and Arf are mutated in a high percentage of human cancer”
Hematopoietic Stem Cell Injury Induced by Ionizing Radiation
Shao, L., Luo, Y., & Zhou, D. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5635 · Cited by 337 · see citing works
“Once SAHF are formed after the engagement of the p16-Rb pathway, the cells become permanently growth arrested and senescent.”
InfluentialA pivotal role for ERK in the oncogenic behaviour of malignant melanoma?
Smalley, K. S. M. (2003) · International Journal of Cancer · doi:10.1002/ijc.10978 · Cited by 320 · see citing works
Cyclin-Dependent Kinase Inhibitors: Useful Targets in Cell Cycle Regulation
Sielecki, T. M., Boylan, J. F., Benfield, P. A., & Trainor, G. L. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990256j · Cited by 321 · see citing works
The INK4 family of cell cycle inhibitors in cancer
Roussel, M. F. (1999) · Oncogene · doi:10.1038/sj.onc.1202998 · Cited by 323 · see citing works
“Several excellent reviews on CKIs (Harper and Elledge, 1996; Nakayama and Nakayama, 1998) and the roles of p16INK4a (Ruas and Peters, 1998) and the INK4a/ARF locus in cancer have been recently published (Sherr, 1998; Sharpless and DePinho, 1999).”
BackgroundBruggeman, S. W. M., Valk-Lingbeek, M. E., van der Stoop, P. P. M., Jacobs, J. J. L., Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., et al. (2005) · Genes & Development · doi:10.1101/gad.1299305 · Cited by 315 · see citing works
“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).”
BackgroundJacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., et al. (2000) · Nature Genetics · doi:10.1038/81583 · Cited by 368 · see citing works
“CDKN2A (p16 INK4a ) is encoded by the CDKN2A ( INK4a/ARF ) tumour suppressor locu”
BackgroundSenescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases
Naylor, R. M., Baker, D. J., & van Deursen, J. M. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.193 · Cited by 280 · see citing works
Cooperative Signals Governing ARF-Mdm2 Interaction and Nucleolar Localization of the Complex
Weber, J. D., Kuo, M.-L., Bothner, B. B., DiGiammarino, E. L., Kriwacki, R. W., Roussel, M. F., & Sherr, C. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.7.2517-2528.2000 · Cited by 273 · see citing works
A critical role for telomeres in suppressing and facilitating carcinogenesis
Artandi, S. E., & DePinho, R. A. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00047-7 · Cited by 318 · see citing works
Self-citationThe INK4a/ARF locus and melanoma
Sharpless, N. E., & Chin, L. (2003) · Oncogene · doi:10.1038/sj.onc.1206461 · Cited by 260 · see citing works
“…locus encodes two distinct proteins, p16INK4a and p14ARF (p19ARF in the mouse), both of which demonstrate tumor suppressor activity in genetically distinct anticancer pathways (i.e. the ‘Rb pathway’ for p16INK4a and the ‘p53 pathway’ for p14ARF) (Ruas and Peters, 1998; Sharpless and DePinho, 1999).”
BackgroundSelf-citationLinggi, B. E., Müller‐Tidow, C., van de Locht, L. T., Hu, M., Nip, J., Serve, H. L., Berdel, W. E., van der Reijden, B., Quelle, D. E., Rowley, J. D., et al. (2002) · Nature Medicine · doi:10.1038/nm726 · Cited by 256 · see citing works
“Therefore, these mRNAs encode two proteins that share identical nucleotide sequence within the second exon, but each has unique coding potentia”
BackgroundAge to survive: DNA damage and aging
Schumacher, B., Garinis, G. A., & Hoeijmakers, J. H. J. (2008) · Trends in Genetics · doi:10.1016/j.tig.2007.11.004 · Cited by 255 · see citing works
Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus
Llanos, S., Clark, P. A., Rowe, J., & Peters, G. G. (2001) · Nature Cell Biology · doi:10.1038/35074506 · Cited by 252 · see citing works
Cellular Senescence: Molecular Mechanisms, In Vivo Significance, and Redox Considerations
Müller, M. K. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2104 · Cited by 237 · see citing works
“Although substantial progress has been made in our understanding of the molecular mechanisms underlying senescence (51, 390, 392, 394, 451), a good deal of uncertainty remains as to the in vivo relevance of senescence and the role it plays in the normal aging process and various pathologic…”
Cell proliferation and apoptosis
Guo, M., & Hay, B. A. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)00046-0 · Cited by 238 · see citing works
Oguro, H., Iwama, A., Morita, Y., Kamijo, T., van Lohuizen, M., & Nakauchi, H. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052477 · Cited by 227 · see citing works
“This results in activation of the p53 target genes involved in cell cycle arrest, apoptosis, or senescence (10).”
INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence
Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P. A., Lomax, M., James, M. C., Vatcheva, R., Bates, S., Vousden, K. H., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf289 · Cited by 220 · see citing works
Role of p14<sup>ARF</sup> in Replicative and Induced Senescence of Human Fibroblasts
Wei, W., Hemmer, R. M., & Sedivy, J. M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.20.6748-6757.2001 · Cited by 217 · see citing works
“This line of reasoning agrees with our observations that Arf, the expression of which is known to respond to signaling imbalances (60), but not DNA damage (65) or oxidative stress (15), is upregulated in senescent rodent cultures but not human cultures.”
ResultSaheb-Al-Zamani, M., Yan, Y., Farber, S. J., Hunter, D. A., Newton, P., Wood, M. D., Stewart, S. A., Johnson, P. J., & Mackinnon, S. E. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.04.011 · Cited by 212 · see citing works
“However, each pathway, while distinct, shares many similar features including triggers and intermediate factors making them difficult to separate (Campisi and d'Adda di Fagagna, 2007; Serrano and Blasco, 2001; Sharpless and DePinho, 1999).”
BackgroundWang, Y., Probin, V., & Zhou, D. (2006) · Current Cancer Therapy Reviews · doi:10.2174/157339406777934717 · Cited by 214 · see citing works
“Activation of Erk/p38 MAPK appears to act downstream of Ras [38,75].”
BackgroundInfluentialTranslational Repression of C. elegans p53 by GLD-1 Regulates DNA Damage-Induced Apoptosis
Schumacher, B., Hanazawa, M., Lee, M., Nayak, S., Volkmann, K., Hofmann, R., Hengartner, M. O., Schedl, T., & Gartner, A. (2005) · Cell · doi:10.1016/j.cell.2004.12.009 · Cited by 214 · see citing works
“Although human cancers commonly contain mutations in the p53 gene itself, many of the remaining tumors have defects in upstream signaling components of the p53 pathway such as inactivation of the positive regulators ARF or CHK2 (Sharpless and DePinho, 1999; Bartek and Lukas, 2003), or overexpression of the negative re…”
BackgroundHuman melanocyte senescence and melanoma susceptibility genes
Bennett, D. C. (2003) · Oncogene · doi:10.1038/sj.onc.1206446 · Cited by 210 · see citing works
“…melanoma susceptibility in humans is found on chromosome 9p21 and is known variously as cyclin-dependent kinase inhibitor 2A (CDKN2A), multiple tumor suppressor 1 (MTS1) or INK4A-ARF (for reviews, see Ruas and Peters, 1998; Sharpless and DePinho, 1999; Hayward, 2000; Rocco and Sidransky, 2001).”
BackgroundBmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming
Zhou, Y., Wang, L., Vaseghi, H. R., Liu, Z., Lu, R., Alimohamadi, S., Yin, C., Fu, J., Wang, G. G., Liu, J., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.02.003 · Cited by 211 · see citing works
“Based on previous reports that Bmi1 and its downstream targets are involved in cell proliferation and senescence (Jacobs et al., 1999; Levine, 1997; Quelle et al., 1995; Sharpless and DePinho, 1999), we sought to determine the requirement of cell proliferation in shBmi1-mediated iCM reprogramming.”
Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208 · see citing works
Zhang, H., Zhai, Z., Wang, Y., Zhang, J., Wu, H., Wang, Y., Li, C., Li, D., Lu, L., Wang, X., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.530 · Cited by 207 · see citing works
“Increased expression of p16 has been widely used as a senescence biomarker and it also functions as an important mediator of cellular senescence induction [24, 25].”
BackgroundDamalas, A., Kahan, S., Shtutman, M. S., Ben‐Ze'ev, A., & Oren, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.17.4912 · Cited by 206 · see citing works
DNA methylation in breast cancer.
Yang, X., Yan, L., & Davidson, N. E. (2001) · Endocrine Related Cancer · doi:10.1677/erc.0.0080115 · Cited by 205 · see citing works
“. These two transcripts share identical second and third exons but have distinct first exons ( Sharpless & DePinho 1999 ).”
Fiore, R. D., D’Anneo, A., Tesoriere, G., & Vento, R. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24329 · Cited by 201 · see citing works
Reactive oxygen species and hematopoietic stem cell senescence
Shao, L., Li, H., Pazhanisamy, S. K., Meng, A., Wang, Y., & Zhou, D. (2011) · International Journal of Hematology · doi:10.1007/s12185-011-0872-1 · Cited by 198 · see citing works
“HSCs from Bmi1−/− mice express increased levels of p16 and Arf [27, 57, 58].”
BackgroundInfluentialDNA methylation in hepatocellular carcinoma
Tischoff, I. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.1741 · Cited by 193 · see citing works
Meng, A., Wang, Y., Zant, G. E. V., & Zhou, D. (2003) · PubMed · Cited by 193 · see citing works
Gartner, A., Boag, P. R., & Blackwell, T. K. (2008) · WormBook · doi:10.1895/wormbook.1.145.1 · Cited by 192 · see citing works
“…fact that most human cancers evolve ways to evade p53 tumor suppressor activity by selecting for mutations in p53 itself, inactivating upstream signaling components (Bartek and Lukas, 2003; Sharpless and DePinho, 1999), or over-expressing negative regulators such as Mdm2 (Freedman et al., 1999).”
The epistemic goal of a concept: accounting for the rationality of semantic change and variation
Brigandt, I. (2009) · Synthese · doi:10.1007/s11229-009-9623-8 · Cited by 189 · see citing works
“…DNA elements code for a product, such as RNA editing and translational recoding (Gray 2003; Baranov et al. 2003), overlapping genes (Mottus et al. 1997), transcription in different reading frames (Sharpless and DePinho 1999), and antisense transcription (Dorn and Krauss 2003; Yelin et al. 2003).”
BackgroundTransient Inactivation of Rb and ARF Yields Regenerative Cells from Postmitotic Mammalian Muscle
Pajcini, K. V., Corbel, S. Y., Sage, J., Pomerantz, J. H., & Blau, H. M. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.05.022 · Cited by 188 · see citing works
“In marked contrast, in similar experiments using primary muscle cells isolated directly from mammalian muscle tissues, Rb reduction or elimination by Cre-mediated excision, failed to result in significant S-phase reentry (Sacco et al. 2003; Camarda et al. 2004; Huh et al. 2004).”
BackgroundResultMolecular markers in oral epithelial dysplasia: review
Pitiyage, G. N., Tilakaratne, W. M., Tavassoli, M., & Warnakulasuriya, S. (2009) · Journal of Oral Pathology and Medicine · doi:10.1111/j.1600-0714.2009.00804.x · Cited by 185 · see citing works
p16Ink4a in Melanocyte Senescence and Differentiation
Sviderskaya, E. V. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.6.446 · Cited by 177 · see citing works
Control of p53 ubiquitination and nuclear export by MDM2 and ARF.
Zhang, Y., & Xiong, Y. (2001) · PubMed · Cited by 176 · see citing works
Epigenetic Control of a Transcription Factor at the Cross Section of Two Antagonistic Pathways
Álvarez-Venegas, R., Al-Abdallat, A. M., Guo, M., Alfano, J. R., & AVRAMOVA, Z. V. (2007) · Epigenetics · doi:10.4161/epi.2.2.4404 · Cited by 171 · see citing works
The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons
Finta, C., & Zaphiropoulos, P. G. (2000) · Gene · doi:10.1016/s0378-1119(00)00470-4 · Cited by 170 · see citing works
p19ARF targets certain E2F species for degradation
Martelli, F., Hamilton, T., Silver, D. P., Sharpless, N. E., Bardeesy, N. M., Rokas, M., DePinho, R. A., Livingston, D. M., & Grossman, S. R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081061398 · Cited by 167 · see citing works
Self-citationShao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D. (2014) · Blood · doi:10.1182/blood-2013-07-515619 · Cited by 165 · see citing works
“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) Therefore, activation of p53 by Arf can induce not only senescence but also apoptosis, depending…”
BackgroundSelf-citationGenetically defined mouse models that mimic natural aspects of human prostate cancer development.
Roy‐Burman, P., Wu, H., Powell, W. C., Hagenkord, J. M., & Cohen, M. B. (2004) · Endocrine Related Cancer · doi:10.1677/erc.0.0110225 · Cited by 164 · see citing works
“The first transgenic mouse line, designed with the anticipation to induce prostate cancer, used a potentially prostate-restricted promoter, that is of the prostate steroid-binding protein C3(1) gene to drive expression of the SV40 viral large T-antigen (Maroulakou et al. 1994, Shibata et al. 1998).”
Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas
Bardeesy, N., Bastian, B. C., Hezel, A., Pinkel, D., DePinho, R. A., & Chin, L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.6.2144-2153.2001 · Cited by 166 · see citing works
“in the absence of germ line ARF-specific mutations in cancerprone kindreds (50).”
BackgroundSelf-citationInvasive melanoma in Cdk4-targeted mice
Sotillo, R., García, J. F., Ortega, S., Martín‐Broto, J., Dubus, P. R., Barbacid, M., & Malumbres, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.241338598 · Cited by 164 · see citing works
Ueda, Y., & Richmond, A. (2006) · Pigment Cell Research · doi:10.1111/j.1600-0749.2006.00304.x · Cited by 148 · see citing works
“…upregulation and p16 INK4a mutation p16 INK4a regulates not only cell proliferation (Hayward, 2000; Rocco and Sidransky, 2001; Ruas and Peters, 1998; Sharpless and DePinho, 1999), but also the activity of the retinoblastoma (RB) protein family members, which are tumor suppressors and inhibitors of…”
BackgroundConstitutive and inducible expression and regulation of vascular endothelial growth factor
Xie, K., Wei, D., Shi, Q., & Huang, S. (2004) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2004.04.003 · Cited by 163 · see citing works
“p16 The Ink4a/Arf4 locus encodes the tumor suppressors p16Ink4a (p16) and p19Arf (Arf) [214].”
BackgroundÁlvarez-Venegas, R., Sadder, M. T., Hlavačka, A., Baluška, F., Xia, Y., Lu, G., Firsov, A., Sarath, G., Moriyama, H., DUBROVSKY, J. G., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600944103 · Cited by 161 · see citing works
Gizard, F., Amant, C., Barbier, O., Bellosta, S., Robillard, R., Percevault, F., Sevestre, H., Krimpenfort, P., Corsini, A., Rochette, J., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22756 · Cited by 159 · see citing works
“Several studies have established that loss of p16 function can be an early event in tumor progression (42, 43) and that it is associated with tumor development (29, 44, 45).”
BackgroundSuppression of p53 by Notch in lymphomagenesis: implications for initiation and regression
Beverly, L. J., Felsher, D. W., & Capobianco, A. J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1664 · Cited by 157 · see citing works
“pathway acts as a tumor surveillance mechanism that is activated in response to inappropriately sustained proliferative signals (21, 22).”
BackgroundCellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b
Malumbres, M., de Castro, I. P., Hernández, M. I., Jiménez, M., Corral, T., & Pellicer, À. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.8.2915-2925.2000 · Cited by 154 · see citing works
Bernhard, D., Tinhofer, I., Tonko, M., Hübl, H., Ausserlechner, M., Greil, R., Kofler, R., & Csordas, A. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400719 · Cited by 156 · see citing works
Role of Polycomb Group Proteins in Stem Cell Self-Renewal and Cancer
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“Whereas p16 Ink4a is a cyclin-dependent kinase inhibitor that activates the Rb pathway through inhibition of cyclin D-Cdk4/6 complexes, Arf induces the p53 pathway by inhibiting Mdm2 function (Sharpless and DePinho, 1999; Sherr, 2001).”
p 21WAF1 C ontrol of E pithelial C ell C ycle and C ell F ate
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“More frequent cancer-associated alterations are deletions, mutations, and methylation of the Ink4a/Arf locus (Kamb et al. 1994; Sherr 1998; Sharpless and DePinho 1999).”
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“63. TAN, R.S., TANIGUCHI, T., and HARADA, H. (1996). Identifi-”
- Authors
- Sharpless, N. E., & DePinho, R. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Corresponding author
- 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)
- 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
- 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
- Health Sciences › Medicine › Physiology › 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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