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

The DOI matches its Crossref record; 82 of the 92 references it cites were found in a registry or an index.

The INK4A/ARF locus and its two gene products.

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1016/s0959-437x(99)80004-5

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Cancer Cell Cycles
Sherr, C. J. (1996) · Science · doi:10.1126/science.274.5293.1672 · Cited by 5,379
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Butel, J. S., & Bradley, A. (1992) · Nature · doi:10.1038/356215a0 · Cited by 4,649
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
Serrano, M., Hannon, G. J., & Beach, D. (1993) · Nature · doi:10.1038/366704a0 · Cited by 3,650
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312
Induction of apoptosis in fibroblasts by c-myc protein
Evan, G. I., Wyllie, A. H., Gilbert, C. S., Littlewood, T. D., Land, H., Brooks, M. W., Waters, C. M., Penn, L. Z., & Hancock, D. C. (1992) · Cell · doi:10.1016/0092-8674(92)90123-t · Cited by 2,941
Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes
Land, H., Parada, L. F., & Weinberg, R. A. (1983) · Nature · doi:10.1038/304596a0 · Cited by 2,804
A cell cycle regulator potentially involved in genesis of many tumor types
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., Johnson, B. E., & Skolnick, M. H. (1994) · Science · doi:10.1126/science.8153634 · Cited by 2,751

Show all 92 references

Sorted by citations

Items 201–300 of 534

CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma
Pastorino, L., Bonelli, L. A., Ghiorzo, P., Queirolo, P., Battistuzzi, L., Balleari, E., Nasti, S., Gargiulo, S., Gliori, S., Savoia, P., et al. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2008.00512.x · Cited by 56
“Genetic risk factors include germline mutations in the high-risk susceptibility genes CDKN2A and CDK4 and in the low penetrance gene MC1R (Sharpless and DePinho, 1999; de Snoo and Hayward, 2005).”
Background
Frequent Deletion and Methylation in SH3GL2 and CDKN2A Loci are Associated with Early- and Late-onset Breast Carcinoma
Sinha, S., Chunder, N., Mukherjee, N., Alam, N., Roy, A. K., Roychoudhury, S., & Panda, C. K. (2008) · Annals of Surgical Oncology · doi:10.1245/s10434-007-9790-0 · Cited by 56
“The p16 and p15 both cause G1-S arrest, inhibiting phosphorylation of retinoblastoma protein (Rb), while p14 arrests cells in both G1 and G2/M phases, inhibiting mdm2-mediated destruction of the p53.(9) Homozygous deletion (HD) in BC cell lines varied from 40–60% in CDKN2A and 21% in CDKN2B.”
Background
Telomere function and regulation from mouse models to human ageing and disease
Jones-Weinert, C. W., Mainz, L., & Karlseder, J. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00800-5 · Cited by 63
“Tumour suppressive functions have been ascribed to all INK4–ARF locus genes, as they are often mutated or lost in cancer 305 .”
H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism
Delgado, M. D., Vaque, J. P., Arozarena, I., Lopez-Ilasaca, M. A., Martínez, C., Crespo, P., & León, J. (2000) · Oncogene · doi:10.1038/sj.onc.1203384 · Cited by 55
“This second pathway impinges in the induction of p19ARF (p14ARF in human cells) (Palmero et al., 1998). p19ARF in turn has been shown to inactivate Mdm2, resulting in high levels of p53 (reviewed in Sharpless and DePinho, 1999).”
Background
Expression of p16INK4A and p14ARF in hematological malignancies
Taniguchi, T., Chikatsu, N., Takahashi, S., Fujita, A., Uchimaru, K., Asano, S., Fujita, T., & Motokura, T. (1999) · Leukemia · doi:10.1038/sj.leu.2401557 · Cited by 55
Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior
Nilsson, K., Svensson, S., & Landberg, G. (2004) · Modern Pathology · doi:10.1038/modpathol.3800220 · Cited by 54
MECHANISMS OF CELL-CYCLE CHECKPOINTS: AT THE CROSSROADS OF CARCINOGENESIS AND DRUG DISCOVERY*
Flatt, P. M., & Pietenpol, J. A. (2000) · Drug Metabolism Reviews · doi:10.1081/dmr-100102335 · Cited by 54
An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis
Kovi, R. C., Paliwal, S., Pande, S., & Grossman, S. R. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.140 · Cited by 53
“mas, malignant glioma, melanoma, and non-Hodgkin’s lymphoma.(4,5) Germline homozygous knockout of Arf in mice results in the development of lymphomas and sarcomas similar to those observed in p53-deficient mice.”
Background
Antiviral action of the tumor suppressor ARF
García, M. Á., Collado, M., Muñoz‐Fontela, C., Matheu, A., Marcos-Villar, L., Arroyo, J., Estéban, M., Serrano, M., & Rivas, C. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601302 · Cited by 56
“One of the most frequently mutated genes in cancer is the product of the Arf gene (Ruas and Peters, 1998; Sharpless and DePinho, 1999).”
Background
Evolutionary etiology of high-grade astrocytomas
Song, Y., Zhang, Q., Kutlu, B., Difilippantonio, S., Bash, R., Gilbert, D. J., Yin, C., O’Sullivan, T. N., Yang, C., Козлов, С. В., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1317026110 · Cited by 55
“In mouse, deletion of INK4A does not elicit brain pathology (29, 30).”
Background
CD30-positive primary cutaneous lymphoproliferative disorders: molecular alterations and targeted therapies
Prieto‐Torres, L., Rodríguez-Pinilla, S. M., Onaindía, A., Ara, M., Requena, L., & Piris, M. A. (2019) · Haematologica · doi:10.3324/haematol.2018.197152 · Cited by 53
Stability of nucleolar versus non-nucleolar forms of human p14ARF
RODWAY, H. A., Llanos, S., Rowe, J., & Peters, G. G. (2004) · Oncogene · doi:10.1038/sj.onc.1207854 · Cited by 53
“Thus, the three proteins engage in a regulatory circuit in which p53 activates transcription of its negative regulator, MDM2, but represses that of its positive regulator, ARF (Sharpless and DePinho, 1999; Sherr, 2001).”
Background
SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit
Ghosh, A., Ghosh, S., Maiti, G. P., Sabbir, M. G., Alam, N., Sikdar, N., Roy, B., Roychoudhury, S., & Panda, C. K. (2008) · The Journal of Pathology · doi:10.1002/path.2464 · Cited by 53
“Both p16 and p15INK4b negatively regulate cell cycle progression at the G1–S checkpoint through the Rb–E2F pathway, while p14ARF blocks the MDM2-mediated degradation of p53, resulting in cell cycle arrest either at G1–S or at G2–M [5].”
Background
Different Requirements for the Cytostatic and Apoptotic Effects of Type I Interferons
Sandoval, R., Xue, J., Pilkinton, M. A., Salvi, D., Kiyokawa, H., & Colamonici, O. R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313830200 · Cited by 53
Deletion at chromosome arm 9p in relation to BRAF/NRAS mutations and prognostic significance for primary melanoma
Conway, C., Beswick, S., Elliott, F., Chang, Y., Randerson‐Moor, J. A., Harland, M., Affleck, P., Marsden, J., Sanders, D. S., Boon, A., et al. (2010) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20753 · Cited by 52
The Clinical Importance of Ki-67, p16, p14, and p57 Expression in Patients With Advanced Ovarian Carcinoma
Khouja, M. H., Baekelandt, M. M. O., Nesland, J. M., & Holm, R. (2007) · International Journal of Gynecological Pathology · doi:10.1097/pgp.0b013e31804216a0 · Cited by 52
“003 Positive (95%) 87 5 (6) 82 (94) 51 (59) 36 (41) Bcl-2 protein Negative (G5%) 106 17 (16) 89 (84) 0.”
Background
Deregulation of the G1 to S-Phase Cell Cycle Checkpoint Is Involved in the Pathogenesis of Human Osteosarcoma
L??pez-Guerrero, J. A., L??pez-Gin??s, C., Pell??n, A., Cardá, C., & Llombart‐Bosch, A. (2004) · Diagnostic Molecular Pathology · doi:10.1097/00019606-200406000-00004 · Cited by 52
“[P14] acts upstream in the p53 pathway by binding to MDM2 and preventing p53 degradation, thus permitting p53induced apoptosis or growth arrest.(17) The p53 protein, whose activity is modulated through its union to MDM2, also impacts on G1 to S progression by increasing expression of another CDKI, p21, which is able t…”
Background
Advances in mouse models of prostate cancer
Ahmad, I., Sansom, O. J., & Leung, H. Y. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000689 · Cited by 50
Dual Role of the Alternative Reading Frame ARF Protein in Cancer
Fontana, R., Ranieri, M., Mantia, G. L., & Vivo, M. (2019) · Biomolecules · doi:10.3390/biom9030087 · Cited by 54
“In this way, the retinoblastoma protein pRB is maintained in an active hypo-phosphorylated state and sequesters the transcription factors of the E2F family causing G1-phase cell cycle arrest [7,8] (Figure 1b).”
Background
Developmental origins and oncogenic pathways in malignant brain tumors
Lu, Q. R., Qian, L., & Zhou, X. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.342 · Cited by 55
“Mutations in genes in the RB pathway (e.g., RB, p16INK4a, and CDK4) result in increased mitotic activity, leading to malignant transformation (Knudsen & Wang, 2010; Sharpless & DePinho, 1999).”
Background
Expression of cell-cycle regulatory proteins and their prognostic value in superficial low-grade urothelial cell carcinoma of the bladder
Santos, L. L., Amaro, T., Pereira, S., Lameiras, C., Lopes, P., Bento, M. J., Oliveira, J., Criado, M. B., & Lopes, C. (2003) · European Journal of Surgical Oncology · doi:10.1053/ejso.2002.1371 · Cited by 51
One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus
Gilley, J., & Fried, M. (2001) · Oncogene · doi:10.1038/sj.onc.1204933 · Cited by 50
“For example, the INK4A/ARF gene is frequently mutated in human cancers and mutation or loss of expression of the INK4B gene as a result of promoter hypermethylation occurs in a number of leukaemias and lymphomas (Ruas and Peters, 1998; Serrano, 2000; Sharpless and DePinho, 1999; Sherr, 1998).”
Background
Detecting overlapping coding sequences with pairwise alignments
Firth, A. E., & Brown, C. M. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bti007 · Cited by 52
“Overlapping CDSs also occur in prokaryotes (Rogozin et al., 2002; Fukuda et al., 2003) and, more rarely, in eukaryotes (Sharpless and DePinho, 1999; Poulin et al., 2003).”
Background
UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis
Ehrhart, J., Gosselet, F., Culerrier, R. M., & Sarasin, A. R. (2003) · Photochemical & Photobiological Sciences · doi:10.1039/b302281a · Cited by 50
MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway
Rao, J. S., Bhoopathi, P., Chetty, C., Gujrati, M., & Lakka, S. S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0380 · Cited by 50
“The induction of these CDK inhibitors has been implicated in the initiation and maintenance of cellular senescence (31, 32).”
Background
Modulation of the expression of p16INK4aand p14ARFby hnRNP A1 and A2 RNA binding proteins: Implications for cellular senescence
Zhu, D., Xu, G., Ghandhi, S., & Hubbard, K. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10147 · Cited by 49
“Both proteins of the INK4a locus have been implicated in the maintenance of replicative senescence and their absence permits cells to escape senescence (Ruas and Peters, 1998; Sherr, 1998; Sharpless and DePinho, 1999).”
Background
Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16 Ink4a
Boquoi, A., Arora, S., Chen, T., Litwin, S., Koh, J., & Enders, G. H. (2014) · Aging Cell · doi:10.1111/acel.12279 · Cited by 52
Correlation between p14ARF/p16INK4A expression and HPV infection in uterine cervical cancer
Kanao, H., Enomoto, T., Ueda, Y., Fujita, M., Nakashima, R., Ueno, Y., Miyatake, T., Yoshizaki, T., Buzard, G. S., Kimura, T., et al. (2004) · Cancer Letters · doi:10.1016/j.canlet.2004.03.030 · Cited by 49
“Co-deletion of p16 and p14 has been reported in some tumor types [14].”
Background
Bmi1 directly represses p21Waf1/Cip1 in Shh-induced proliferation of cerebellar granule cell progenitors
Subkhankulova, T., Zhang, X., Leung, C., & Marino, S. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.06.006 · Cited by 50
Emerging Biomarkers in Cutaneous Melanoma
Eisenstein, A. S., Gonzalez, E. C., Raghunathan, R., Xu, X., Wu, M., McLean, E. O., McGee, J. S., Ryu, B., & Alani, R. M. (2018) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-018-0318-z · Cited by 48
“deletion on chromosome 9p21, which is known to contain the CDKN2A and CDKN2B genes, which encode tumor suppressor proteins [90].”
Background
Common chromosomal abnormalities in mycosis fungoides transformation
Procházková, M., Chevret, E., Mainhaguiet, G., Sobotka, J., Vergier, B., Belaud‐Rotureau, M., Beylot-Barry, M., & Merlio, J. (2007) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20469 · Cited by 47
Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression
Zhou, Y., Nakajima, R., Shirasawa, M., Fikriyanti, M., Zhao, L., Iwanaga, R., Bradford, A. P., Kurayoshi, K., Araki, K., & Ohtani, K. (2023) · Biology · doi:10.3390/biology12121511 · Cited by 52
“Hence, p16 and p14 ARF play crucial roles in tumor surveillance [79–81] (Figure 4).”
Background
Tumor Suppressors and Cell-Cycle Proteins in Lung Cancer
Baldi, A., Luca, A. D., Esposito, V., Campioni, M., Spugnini, E. P., & Citro, G. (2011) · Pathology Research International · doi:10.4061/2011/605042 · Cited by 45
“Likewise, many human breast cancers have reduced p27Kip1 protein expression or aberrant subcellular localization of the protein that has been correlated with more aggressive tumors [72, 73].”
Background
Modeling prostate cancer: a perspective on transgenic mouse models
Jeet, V., Russell, P. J., & Khatri, A. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9212-9 · Cited by 46
“The Ink4a/Arf gene locus controls the expression of tumor suppressor genes, p16 and p19, which further regulate the activities of p53 and Rb pathways [119].”
Background
Environmental UV Radiation: Impact on Ecosystems and Human Health and Predictive Models
Ghetti, F., Bornman, J. F., & Checcucci, G. (2006) · NATO science series. Series IV, Earth and environmental sciences · doi:10.1007/1-4020-3697-3 · Cited by 46
Epigenetic Regulation of Hematopoietic Stem Cell Self-Renewal by Polycomb Group Genes
Iwama, A., Oguro, H., Negishi, M., Kato, Y., & Nakauchi, H. (2005) · International Journal of Hematology · doi:10.1532/ijh97.05011 · Cited by 46
“This locus encodes a CKI, p16 INK4A , and a tumor suppressor, p19 ARF . p16 INK4A inhibits the binding of cyclin D to Cdk4/6 complexes and keeps the retinoblastoma protein hypophosphorylated (Figure 3). Hypophosphorylated retinoblastoma protein represses E2F-dependent transcription by sequestering E2F, ultimately lead…”
Background
The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells
Abdouh, M., Hanna, R., Hajjar, J. E., Flamier, A., & Bernier, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.662403 · Cited by 48
Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma
Ghiorzo, P., Gargiulo, S., Pastorino, L., Nasti, S., Cusano, R., Bruno, W., Gliori, S., Sertoli, M. R., Burroni, A. G., Savarino, V., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl199 · Cited by 46
Interferon-Inducible Protein IFIXα1 Functions as a Negative Regulator of HDM2
Ding, Y., Lee, J.-F., Lu, H., Lee, M., & Yan, D. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.5.1979-1996.2006 · Cited by 44
“, p14ARF (70, 82), MDMX (32, 74), TSG101 (50), and HAUSP (51).”
Bmi-1 regulates self-renewal, proliferation and senescence of human fetal neural stem cells in vitro
Wang, Y., Guan, Y., Wang, F., Huang, A., Wang, S., & Zhang, Y. A. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.04.006 · Cited by 47
The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models
Yen, J. L., White, R. M., Wedge, D. C., Loo, P. V., de Ridder, J., Capper, A., Richardson, J., Jones, D., Raine, K. M., Watson, I. R., et al. (2013) · Genome biology · doi:10.1186/gb-2013-14-10-r113 · Cited by 46
“While p53 itself has not traditionally been considered to be a major tumor suppressor in melanoma development, inactivation of CDKN2A/p16 is associated with loss of p53 activity [13].”
Background
Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells
Hemmati, P., Güner, D., Gillissen, B. F., Wendt, J., von Haefen, C., Chinnadurai, G., Dörken, B., & Daniel, P. T. (2006) · Oncogene · doi:10.1038/sj.onc.1209668 · Cited by 44
“Therefore, it was suggested that p14ARF primarily utilizes the mdm-2/p53 signaling axis (Sharpless and DePinho, 1999; Sherr, 2001).”
Background
Pex19p Dampens the p19ARF-p53-p21WAF1 Tumor Suppressor Pathway*
Sugihara, T., Kaul, S. C., Kato, J., Reddel, R. R., Nomura, H., & Wadhwa, R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100011200 · Cited by 44
Advances in oncolytic adenovirus therapy for pancreatic cancer
Nattress, C. B., & Halldén, G. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.07.006 · Cited by 43
Animal models of melanoma: Recent advances and future prospects
Bardeesy, N. M., Wong, K., DePinho, R. A., & Chin, L. (2000) · Advances in cancer research · doi:10.1016/s0065-230x(00)79004-x · Cited by 43
Self-citation
Role of Epigenetics in Uveal Melanoma
Li, Y., Jia, R., & Ge, S. (2017) · International Journal of Biological Sciences · doi:10.7150/ijbs.18331 · Cited by 41
“p16/INK4a / Stabilizer of the tumor suppressor protein [8, 44-52]”
Background
Unraveling the complex regulation of stem cells: implications for aging and cancer
Oakley, E. J., & Zant, G. E. V. (2007) · Leukemia · doi:10.1038/sj.leu.2404530 · Cited by 42
Quantitative Proteomics Profiling of Murine Mammary Gland Cells Unravels Impact of Annexin-1 on DNA Damage Response, Cell Adhesion, and Migration
Swa, H. L. F., Blackstock, W. P., Lim, L. H. K., & Gunaratne, J. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.011205 · Cited by 40
“Another important protein that is positively regulated by ANXA1 is p19ARF, the homologue of p14ARF in humans, which is another important tumor suppressor gene (30) regulating the cell cycle and p53 pathways (31).”
Background
The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability
Fitieh, A. M., Locke, A. J., Motamedi, M., & Ismail, I. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062976 · Cited by 43
Epigenetic Down-Regulation of ARF Expression Is a Selection Step in Immortalization of Human Fibroblasts by c-Myc
Benanti, J. A., Wang, M. L., Myers, H. E., Robinson, K. L., Grandori, C., & Galloway, D. A. (2007) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0372 · Cited by 39
“The INK4a/ARF locus encodes two tumor suppressors, p16 and ARF, and undergoes frequent disruption in human cancers (14, 15).”
Background
The Complex Interplay between Nevi and Melanoma: Risk Factors and Precursors
Shreberk‐Hassidim, R., Ostrowski, S. M., & Fisher, D. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043541 · Cited by 45
“This locus encodes two tumor suppressor gene products, including the cell-cycle inhibitor p16 (INK4A) and p14 (ARF), which prevents the degradation of p53 [54,55].”
Background
Canine Mammary Carcinomas: A Comparative Analysis of Altered Gene Expression
Kabir, F. M. L., Alvarez, C. E., & Bird, R. (2015) · Veterinary Sciences · doi:10.3390/vetsci3010001 · Cited by 44
“p53 normally acts as a strong transcriptional activator of p21/Cip1 protein [38].”
Background
Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus.
Gibson, S. L., Dai, C. Y., Lee, H. W., DePinho, R. A., Gee, M. S., Lee, W. M. F., Furth, E. E., Brensinger, C. M., & Enders, G. H. (2003) · PubMed · Cited by 39
Self-citation
Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2
Clark, P. A., Llanos, S., & Peters, G. G. (2002) · Oncogene · doi:10.1038/sj.onc.1205558 · Cited by 39
“…impact of these lesions remains uncertain, however, because p14ARF is encoded by an unusual locus in which a common second exon is decoded in di erent reading frames to produce two structurally and functionally distinct proteins (Ruas and Peters, 1998; Sharpless and DePinho, 1999; Sherr, 1998).”
Background
Induction of Nevi and Skin Tumors in Ink4a/Arf Xpa Knockout Mice by Neonatal, Intermittent, or Chronic UVB Exposures
van Schanke, A., van Venrooij, G. M. C. A. L., Jongsma, M. J., Banus, H. A., Mullenders, L. H. F., van Kranen, H. J., & de Gruijl, F. R. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2476 · Cited by 38
Involvement of activation-induced cytidine deaminase in skin cancer development
NONAKA, T., Toda, Y., Hiai, H., Uemura, M., Nakamura, M., Yamamoto, N., Asato, R., Hattori, Y., Bessho, K., Minato, N., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81522 · Cited by 37
Demethylation of an NF-κB enhancer element orchestrates iNOS induction in osteoarthritis and is associated with altered chondrocyte cell cycle
de Andrés, M. C., Takahashi, A., & Oreffo, R. O. C. (2016) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2016.06.002 · Cited by 37
Recent Advances in the Biology, Therapy and Management of Melanoma
Davids, L. M. (2013) · InTech eBooks · doi:10.5772/46052 · Cited by 38
Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins
Zencak, D., Schouwey, K., Chen, D., Ekström, P. A. R., Tanger, E., Bremner, R., van Lohuizen, M., & Arsenijévic, Y. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108297110 · Cited by 38
CpG Island Methylation Is Responsible for p14ARF Inactivation and Inversely Correlates with p53 Overexpression in Resected Non–Small Cell Lung Cancer
Hsu, H., Wang, Y.-C., Tseng, R., Chang, J.-W., Chen, J.-T., Shih, C., Chen, C., & Wang, Y. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0704 · Cited by 37
“The other product, P14ARF, is encoded by the smaller transcript, which is composed of exons 1 , 2, and 3 (2).”
Background
Role for PP2A in ARF signaling to p53
Moule, M. G., Collins, C. H., McCormick, F. P., & Fried, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405533101 · Cited by 37
The Inhibitor of Cyclin-Dependent Kinase 4a/Alternative Reading Frame ( INK4a/ARF ) Locus Encoded Proteins p16INK4a and p19ARF Repress Cyclin D1 Transcription through Distinct cis Elements
D’Amico, M., Wu, K., Fu, M., Rao, M., Albanese, C., Russell, R. G., Lian, H., Bregman, D. B., White, M. A., & Pestell, R. G. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2519 · Cited by 38
“The INK4a/ARF locus is involved in both the pRb and p53 pathways encoding p16, a regulator of cdk4/6-mediated pRB phosphorylation, and p19, a modulator of Mdm2-mediated degradation of p53 (19, 20).”
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model
Bardeesy, N. M., Sharpless, N. E., DePinho, R. A., & Merlino, G. T. (2001) · Seminars in Cancer Biology · doi:10.1006/scbi.2000.0371 · Cited by 35
Self-citation
Bioinformatics prediction of overlapping frameshifted translation products in mammalian transcripts
Ribrioux, S., Brüngger, A., Baumgarten, B. U., Seuwen, K., & John, M. R. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-122 · Cited by 35
MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer
Niu, T., Zhang, W., & Xiao, W. (2021) · Cancer Cell International · doi:10.1186/s12935-020-01716-8 · Cited by 35
Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2
Palmero, I., Murga, M., Zubiaga, A. M., & Serrano, M. (2002) · Oncogene · doi:10.1038/sj.onc.1205371 · Cited by 35
“The products of the INK4a/ARF locus play a pivotal role as sensors of oncogenic stress (reviewed in Sharpless and DePinho, 1999; Serrano, 2000; Sherr and DePinho, 2000; Sherr and Weber, 2000; Sherr, 2001a, b).”
Background
Retinoic acid causes cell growth arrest and an increase in p27 in F9 wild type but not in F9 retinoic acid receptor β2 knockout cells
Li, R., Faria, T. N., Boehm, M., Nabel, E. G., & Gudas, L. J. (2003) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.11.014 · Cited by 35
“The p16 protein plays an important role in some cell types in regulating cell growth and exhibits tumor suppressor activities [78].”
Background
Genomic p16 abnormalities in the progression of chronic myeloid leukemia into blast crisis
Hernández‐Boluda, J. C., Cervantes, F., Colomer, D., Vela, M.-C., Costa, D., Paz, M. F., Esteller, M., & Montserrat, E. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(02)01075-5 · Cited by 35
Death associated protein kinase: From regulation of apoptosis to tumor suppressive functions and B cell malignancies
Ng, M. H. L. (2002) · APOPTOSIS · doi:10.1023/a:1015364104672 · Cited by 35
Disruption of the Cockayne Syndrome B Gene Impairs Spontaneous Tumorigenesis in Cancer-Predisposed Ink4a/ARF Knockout Mice
Lu, Y., Lian, H., Sharma, P., Schreiber‐Agus, N., Russell, R. G., Chin, L., van der Horst, G. T. J., & Bregman, D. B. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1810-1818.2001 · Cited by 34
Induction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading frame.
Yang, J., Luan, J., Yu, Y., Li, C., DePinho, R. A., Chin, L., & Richmond, A. J. (2001) · PubMed · Cited by 33
Self-citation
FAMMM Syndrome: Pathogenesis and Management
Czajkowski, R., Placek, W. J., Drewa, G., Czajkowska, A., & Uchańska, G. (2004) · Dermatologic Surgery · doi:10.1111/j.1524-4725.2004.30088.x · Cited by 32
“The locus is not drawn to scale.(20) Dermatol Surg 30:2 Part 2:February 2004 CZAJKOWSKI ET AL.”
Background
Immunohistochemical staining for p16 is a useful adjunctive test in the diagnosis of Bowen’s disease
Harvey, N. T., Leecy, T. N., & Wood, B. A. (2013) · Pathology · doi:10.1097/pat.0b013e328360c064 · Cited by 32
“This blockade leads to decreased phosphorylation of retinoblastoma protein (pRB) with subsequent arrest in the G1 phase of the cell cycle.(5) Immunohistochemical staining for p16 is well established as an adjunctive tool in the diagnosis of squamous dysplasia in the cervix.”
Background
Characterization of Coordinated Immediate Responses by p16INK4A and p53 Pathways in UVB-Irradiated Human Skin Cells
Elmageed, Z. Y. A., Gaur, R. L., Williams, M., Abdraboh, M. E., Rao, P. N., Raj, M. H. G., Ismail, F. M., & Ouhtit, A. (2008) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.208 · Cited by 32
“Thus, these models have helped identify the components of Rb pathway as the principal and rate-limiting targets of UV’s actions in melanoma formation (Sharpless and DePinho, 1999; Recio et al., 2002).”
BackgroundResult
Mutational analysis of N-ras, p53, CDKN2A (p16INK4a), p14ARF, CDK4, and MC1R genes in human dysplastic melanocytic naevi
Papp, T. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.2.e14 · Cited by 32
Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis
Walter, L., Pujada, A., Bhatnagar, N., Bialkowska, A. B., Yang, V. W., Laroui, H., & Garg, P. (2016) · Oncotarget · doi:10.18632/oncotarget.13406 · Cited by 32
Cyclin-dependent kinase inhibitors in malignant hematopoiesis
Schirripa, A., Sexl, V., & Kollmann, K. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.916682 · Cited by 39
“Thus, the INK4a locus represents a master growth regulator through its capacity to interface with both proliferation (Rb pathway via p16INK4a) and apoptosis (p53 pathway via p19ARF) (4, 44).”
Background
Mtbp haploinsufficiency in mice increases tumor metastasis
Iwakuma, T., Tochigi, Y., Pelt, C. S. V., Caldwell, L. C., Terzian, T., Parant, J. M., Chau, G. P., Koch, J. G., Eischen, C. M., & Lozano, G. (2007) · Oncogene · doi:10.1038/sj.onc.1210827 · Cited by 31
A Major Functional Difference between the Mouse and Human ARF Tumor Suppressor Proteins
Wadhwa, R., Sugihara, T., Hasan, M. K., Taira, K., Reddel, R. R., & Kaul, S. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203222200 · Cited by 31
The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia
González‐Gil, C., Ribera, J., Ribera, J., & Genescà, E. (2021) · Genes · doi:10.3390/genes12010079 · Cited by 32
“Intriguingly, the CDKNA/B locus encodes a second, structurally and functionally unrelated protein, the alternative reading frame (ARF) or P14ARF, which is also a potent tumor suppressor [4,5].”
Background
Adult neural stem cells and their role in brain pathology
Yadırgı, G., & Marino, S. (2008) · The Journal of Pathology · doi:10.1002/path.2480 · Cited by 30
“During the G1 phase of the cell cycle, p16 directly inhibits cooperation of cyclin D1 and cyclin D-dependent kinases 4/6 (Cdk4/6), which, when unblocked, form a complex that phosphorylates retinoblastoma protein (pRB) [45].”
Background
Piecing together the significance of splicing
Sorek, R., & Amitai, M. (2001) · Nature Biotechnology · doi:10.1038/85613 · Cited by 30
Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb-independent pathway
Tyagi, E., Liu, B., Li, C., Liu, T., Rutter, J. P., & Grossman, D. (2017) · Oncotarget · doi:10.18632/oncotarget.19862 · Cited by 32
“The p16CDKN2A protein (hereafter referred to as p16) binds cyclin-dependent kinases (CDK) to prevent their phosphorylation of the retinoblastoma (Rb) protein which sequesters E2F transcription factors that control transcription of S-phase genes [2].”
Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells
Shima, H., Takamatsu-Ichihara, E., Shino, M., Yamagata, K., Katsumoto, T., Aikawa, Y., Fujita, S., Koseki, H., & Kitabayashi, I. (2018) · Blood · doi:10.1182/blood-2017-05-787226 · Cited by 29
Alterations of 9p21 analysed by FISH and MLPA distinguish atypical spitzoid melanocytic tumours from conventional Spitz’s nevi but do not predict their biological behaviour
Cesinaro, A. M., Schirosi, L., Bettelli, S. R., Migaldi, M., & Maiorana, A. (2010) · Histopathology · doi:10.1111/j.1365-2559.2010.03653.x · Cited by 29
CDKN2A and MC1R analysis in amelanotic and pigmented melanoma
Ghiorzo, P., Pastorino, L., Pizzichetta, M. A., BONO, R., Queirolo, P., Talamini, R., Annessi, G., Bruno, W., Nasti, S., Gargiulo, S., et al. (2009) · Melanoma Research · doi:10.1097/cmr.0b013e32832a1e18 · Cited by 29
The flexible evolutionary anchorage-dependent Pardee's restriction point of mammalian cells. How its deregulation may lead to cancer
David-Pfeuty, T. (2005) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2005.08.008 · Cited by 29
Familial Melanoma–Associated Mutations in p16 Uncouple its Tumor-Suppressor Functions
Jenkins, N., Jung, J., Liu, T., Wilde, M., Holmen, S. L., & Grossman, D. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.401 · Cited by 31
“, 2011) demonstrating sufficiency of p16 in mediating control of intracellular oxidative stress was performed in fibroblasts deficient in CDKN2A, which encodes both the p16 and alternative reading frame (Arf, p19) proteins (Sharpless and DePinho, 1999).”
BackgroundInfluential
Increased expression of the INK4a/ARF locus in polycythemia vera
Dai, C., & Krantz, S. B. (2001) · Blood · doi:10.1182/blood.v97.11.3424 · Cited by 29
Clinical significance of p53 functional loss in squamous cell carcinoma of the oropharynx
Obata, A., Eura, M., Sasaki, J., Saya, H., Chikamatsu, K., Tada, M., Iggo, R. D., & Yumoto, E. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000320)89:2 · Cited by 58
Expression of p15 and p15.5 products in neuroendocrine lung tumours: relationship with p15INK4b methylation status
Chaussade, L., Eymin, B., Brambilla, E. M., & Gazzéri, S. (2001) · Oncogene · doi:10.1038/sj.onc.1204798 · Cited by 29
“…from a complex gene structure, the INK4a/ ARF locus, that also encodes the p14ARF protein implicated in the p53 signalling pathway (for review see Sharpless and DePinho, 1999; Sherr, 1998; Chin et al., 1998). p15INK4b displays high homology to p16INK4a and maps in tandem to the INK4a/ARF locus…”
Background
Profiles of the 2 INK4a gene products, p16 and p14ARF, in human reference urothelium and bladder carcinomas, according to pRb and p53 protein status*1
Frère‐Belda, M. L. (2004) · Human Pathology · doi:10.1016/j.humpath.2004.01.019 · Cited by 28
Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas
Kiss, N. B., Geli, J., Lundberg, F. E., Avcı, Ç. B., Velázquez‐Fernández, D., Hashemi, J., Weber, G., Höög, A., Ekstrom, T. J., Bäckdahl, M., et al. (2008) · Endocrine Related Cancer · doi:10.1677/erc-07-0285 · Cited by 28
“1). p16 and p14 proteins have important functions in cell-cycle regulation (Serrano et al. 1993, Sharpless & DePinho 1999) and generally function as negative regulators of cell-cycle progression. p16INK4A acts mainly via the retinoblastoma (RB) pathway by inhibiting the cyclin-dependent kinases…”
Background
An Inducible Melanoma Model Implicates a Role for RAS in Tumor Maintenance and Angiogenesis
Wong, A. K., & Chin, L. (2000) · Cancer and Metastasis Reviews · doi:10.1023/a:1026537423753 · Cited by 28
“The existence of germline p16 specific exon 1 α mutations in familial melanoma kindreds has conclusively established that p16 INK4a is a bona fidetumor suppressor in humans ([15,16]; see also [9,17]).”
Background
Transgenic Expression of the p16 INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes
Lagresle, C., Gardie, B., Eyquem, S., Fasseu, M., Vieville, J.-C., Pla, M., Sigaux, F., & Bories, J.-C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.5.2325 · Cited by 28
Genetic dissection of melanoma pathways in the mouse
Yang, F. C., Merlino, G. T., & Chin, L. (2001) · Seminars in Cancer Biology · doi:10.1006/scbi.2000.0376 · Cited by 28
Spontaneous Uveal Amelanotic Melanoma in Transgenic Tyr-RAS+ Ink4a/Arf−/− Mice
Tolleson, W. H. (2005) · Archives of Ophthalmology · doi:10.1001/archopht.123.8.1088 · Cited by 27
“Initiating from exon 1 and splicing onto exons 2 to 3, the locus encodes for p16Ink4a, the founding member of the Ink4 family of cyclin-dependent kinase inhibitors upstream of the retinoblastoma protein.(21) Alternatively, initiating from an upstream exon 1 and splicing onto exons 2 to 3 but in a different reading fra…”
Background
Neural stem cells, tumour stem cells and brain tumours: Dangerous relationships?
SUTTER, R., Yadırgı, G., & Marino, S. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2007.07.006 · Cited by 28
Interferon-β induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells
Vannucchi, S., Percario, Z. A., Chiantore, M. V., Matarrese, P., Chelbi‐Alix, M. K., Fagioli, M., Pelicci, P. G., Malorni, W., Fiorucci, G., Romeo, G., et al. (2000) · Oncogene · doi:10.1038/sj.onc.1203883 · Cited by 27
“The control of cell proliferation is increasingly being seen as a result of the signaling mechanisms leading to growth stimulation (Wolthuis and Bos, 1999), growth inhibition or death induced by tumour suppressor genes (Sharpless and DePinho, 1999).”
Background
The ARF/Oncogene Pathway Activates p53 Acetylation within the DNA Binding Domain
Mellert, H. S., Sykes, S. M., Murphy, M. E., & McMahon, S. B. (2007) · Cell Cycle · doi:10.4161/cc.6.11.4343 · Cited by 32

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

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 ›

Are you an author, or do you see a problem with this page? Request a review

The INK4A/ARF locus and its two gene products.

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks