The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53
Open accessAbstract
The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19Arf and MDM2 physically interact and that p19Rrf blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19Arf functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
p19Arf inhibits Mdm2-mediated degradation of p53 and is required for activation of p53 in response to aberrant cell cycle entry and oncogene activation.
“p19 Arf has been shown to inhibit Mdm2-mediated degradation of p53 (19-21) and is clearly required for activation of p53 in response to aberrant cell cycle entry (19) and oncogene activation (22-24).”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [19]
Under most conditions, ARF functions as a tumor suppressor by binding and inhibiting Mdm2 activity.
“Under most conditions ARF functions as a tumor suppressor by binding and inhibiting Mdm2 activity [47–49].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [48]
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
p53 Mutations in Human Cancers
Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991) · Science · doi:10.1126/science.1905840 · Cited by 8,018 · see citing works
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 · see citing works
Recombinant Genomes Which Express Chloramphenicol Acetyltransferase in Mammalian Cells
Gorman, C., Moffat, L. F., & Howard, B. H. (1982) · Molecular and Cellular Biology · doi:10.1128/mcb.2.9.1044 · Cited by 7,673 · see citing works
Sherr, C. J. (1996) · Science · doi:10.1126/science.274.5293.1672 · Cited by 5,379 · see citing works
The retinoblastoma protein and cell cycle control
Weinberg, R. A. (1995) · Cell · doi:10.1016/0092-8674(95)90385-2 · Cited by 4,862 · see citing works
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 · see citing works
The p53 tumour suppressor gene
Levine, A. J., Momand, J. A., & Finlay, C. A. (1991) · Nature · doi:10.1038/351453a0 · Cited by 3,785 · see citing works
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 · see citing works
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 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
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 · see citing works
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 · see citing works
p53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · see citing works
The p53 proto-oncogene can act as a suppressor of transformation
Finlay, C. A., Hinds, P. W., & Levine, A. J. (1989) · Cell · doi:10.1016/0092-8674(89)90045-7 · Cited by 1,987 · see citing works
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949 · see citing works
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626 · see citing works
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585 · see citing works
Self-citationTumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566 · see citing works
Ouelle, D. E., Zindy, F., Ashmun, R. A., & Sherr, C. J. (1995) · Cell · doi:10.1016/0092-8674(95)90214-7 · Cited by 1,485 · see citing works
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · see citing works
Münger, K., Phelps, W. C., Bubb, V. J., Howley, P. M., & Schlegel, R. (1989) · Journal of Virology · doi:10.1128/jvi.63.10.4417-4421.1989 · Cited by 1,335 · see citing works
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · see citing works
HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes.
Hawley‐Nelson, P., Vousden, K. H., Hubbert, N. L., Lowy, D. R., & Schiller, J. T. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08570.x · Cited by 914 · see citing works
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16
Lukas, J., Parry, D., Aagaard, L., Mann, D. J., Bartkova, J., Strauss, M., Peters, G., & Bartek, J. (1995) · Nature · doi:10.1038/375503a0 · Cited by 899 · see citing works
p53-Dependent apoptosis suppresses tumor growth and progression in vivo
Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T., & Van Dyke, T. (1994) · Cell · doi:10.1016/0092-8674(94)90534-7 · Cited by 880 · see citing works
Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression
Alland, L., Muhle, R., Hou, H., Potes, J., Chin, L., Schreiber‐Agus, N., & DePinho, R. A. (1997) · Nature · doi:10.1038/387049a0 · Cited by 841 · see citing works
Self-citationGermline mutations in the p16INK4a binding domain of CDK4 in familial melanoma
Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., Walker, G. J., Hayward, N., & Dracopoli, N. C. (1996) · Nature Genetics · doi:10.1038/ng0196-97 · Cited by 818 · see citing works
Fakharzadeh, S. S., Trusko, S. P., & George, D. L. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07676.x · Cited by 704 · see citing works
Wild-type p53 can inhibit oncogene-mediated focus formation.
Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O., & Oren, M. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.8763 · Cited by 681 · see citing works
p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens
Morgenbesser, S. D., Williams, B. O., Jacks, T., & DePinho, R. A. (1994) · Nature · doi:10.1038/371072a0 · Cited by 607 · see citing works
Self-citationInteraction between the retinoblastoma protein and the oncoprotein MDM2
Xiao, Z.-X., Chen, J., Levine, A. J., Modjtahedi, N., Xing, J. W., Sellers, W. R., & Livingston, D. M. (1995) · Nature · doi:10.1038/375694a0 · Cited by 586 · see citing works
Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia.
Cordon‐Cardo, C. (1995) · PubMed Central · Cited by 532 · see citing works
Self-citationp53 in growth control and neoplasia
Gottlieb, T. M., & Oren, M. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00019-c · Cited by 481 · see citing works
Growth suppression by p16ink4 requires functional retinoblastoma protein
Medema, R. H., Herrera, R. E., Lam, F., & Weinberg, R. A. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6289 · Cited by 433 · see citing works
Sequence-specific transcriptional activation is essential for growth suppression by p53.
Pietenpol, J. A., Tokino, T., Thiagalingam, S., El‐Deiry, W. S., Kinzler, K. W., & Vogelstein, B. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.6.1998 · Cited by 406 · see citing works
Cooperative effects of INK4a and ras in melanoma susceptibility in vivoPreprint
Chin, L., Pomerantz, J. H., Polsky, D., Jacobson, M., Cohen, C., Cordon‐Cardo, C., Horner, J. W., & DePinho, R. A. (1997) · Genes & Development · doi:10.1101/gad.11.21.2822 · Cited by 403 · see citing works
Self-citationInhibition of Ras-Induced Proliferation and Cellular Transformation by p16 INK4
Serrano, M., Gómez-Lahoz, E., DePinho, R. A., Beach, D., & Bar‐Sagi, D. (1995) · Science · doi:10.1126/science.7809631 · Cited by 373 · see citing works
Self-citationCooperative tumorigenic effects of germline mutations in Rb and p53
Williams, B. O., Remington, L., Albert, D. M., Mukai, S., Bronson, R. T., & Jacks, T. (1994) · Nature Genetics · doi:10.1038/ng0894-480 · Cited by 367 · see citing works
Schreiber‐Agus, N., Chin, L., Chen, K., Torres, R., Rao, G., Guida, P. M., Skoultchi, A. I., & DePinho, R. A. (1995) · Cell · doi:10.1016/0092-8674(95)90356-9 · Cited by 361 · see citing works
Self-citationCAHILLY, L. A., Yang‐Feng, T. L., Francke, U., & George, D. L. (1987) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01535205 · Cited by 355 · see citing works
Barak, Y., Gottlieb, E., Juven-Gershon, T., & Oren, M. (1994) · Genes & Development · doi:10.1101/gad.8.15.1739 · Cited by 328 · see citing works
The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth.
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301 · Cited by 311 · see citing works
The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis.
Bártková, J., Lukáš, J., Guldberg, P., Alsner, J., Kirkin, A. F., Zeuthen, J., & Bártek, J. (1996) · PubMed · Cited by 275 · see citing works
Repression of p53-mediated transcription by MDM2: a dual mechanism
Thut, C. J., Goodrich, J. A., & Tjian, R. (1997) · Genes & Development · doi:10.1101/gad.11.15.1974 · Cited by 272 · see citing works
Transcriptional activation by p53 correlates with suppression of growth but not transformation
Crook, T. J. (1994) · Cell · doi:10.1016/0092-8674(94)90071-x · Cited by 233 · see citing works
Quelle, D. E., Cheng, M. M., Ashmun, R. A., & Sherr, C. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.2.669 · Cited by 217 · see citing works
Regulation of Transcription Functions of the p53 Tumor Suppressor by the mdm-2 Oncogene
Chen, J., Lin, J., & Levine, A. J. (1995) · Molecular Medicine · doi:10.1007/bf03401562 · Cited by 214 · see citing works
Oncogenesis of the Lens in Transgenic Mice
Mahon, K. A., Chepelinsky, A. B., Khillan, J. S., Overbeek, P. A., Piatigorsky, J., & Westphal, H. (1987) · Science · doi:10.1126/science.3029873 · Cited by 194 · see citing works
Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes.
Olson, D. C., Maréchal, V., Momand, J. A., Chen, J., Romocki, C., & Levine, A. J. (1993) · PubMed · Cited by 188 · see citing works
Simian virus 40 large T antigen: the puzzle, the pieces, and the emerging picture
Fanning, E. (1992) · Journal of Virology · doi:10.1128/jvi.66.3.1289-1293.1992 · Cited by 168 · see citing works
Suppression of Myc, but not E1a, transformation activity by Max-associated proteins, Mad and Mxi1.
Lahoz, E. G., Xu, L., Schreiber‐Agus, N., & DePinho, R. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.12.5503 · Cited by 119 · see citing works
Self-citationHangaishi, A., Ogawa, S., Imamura, N., Miyawaki, S., Miura, Y., Uike, N., Shimazaki, C., Emi, N., Takeyama, K., Hirosawa, S., et al. (1996) · Blood · doi:10.1182/blood.v87.12.4949.bloodjournal87124949 · Cited by 115 · see citing works
Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Frye, C., Eeles, R. A., Orlow, I., Lacombe, L., Ponce-Castañeda, V., LIANES, P., & Latres, E. (1995) · Europe PMC (PubMed Central) · Cited by 113 · see citing works
Self-citationA question of balance: the role of cyclin-kinase inhibitors in development and tumorigenesis
Elledge, S. J., Winston, J. T., & Harper, J. W. (1996) · Trends in Cell Biology · doi:10.1016/0962-8924(96)10030-1 · Cited by 113 · see citing works
Kinoshita, I., Dosaka‐Akita, H., Mishina, T., Akie, K., Nishi, M., Hiroumi, H., Hommura, F., & Kawakami, Y. (1996) · PubMed · Cited by 78 · see citing works
Heinzel, P. A., Balaram, P., & Bernard, H. (1996) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19961115)68:4 · Cited by 70 · see citing works
Preferential loss of expression of p16(INK4a) rather than p19(ARF) in breast cancer.
Brenner, A. J., Paladugu, A. V., Wang, H., Olopade, O. I., Dreyling, M. H., & Aldaz, C. M. (1996) · PubMed · Cited by 58 · see citing works
Brown, D. R., Deb, S., Muñoz, R. M., Subler, M. A., & Deb, S. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.11.6849 · Cited by 58 · see citing works
Analysis of viral-host protein interactions and tumorigenesis in transgenic mice.
Ta, V. D. (1994) · PubMed · Cited by 31 · see citing works
MDM2 is a target of simian virus 40 in cellular transformation and during lytic infection
Henning, W., Rohaly, G., Kolzau, T., Knippschild, U., Maacke, H., & Deppert, W. (1997) · Journal of Virology · doi:10.1128/jvi.71.10.7609-7618.1997 · Cited by 29 · see citing works
Schreiber‐Agus, N., Chin, L., Chen, K., TORRES, R. A., Thomson, C. T., Sacchettini, J. C., & DePinho, R. A. (1994) · PubMed · Cited by 25 · see citing works
Self-citationNewcomb, E. W., Rao, L. S., Giknavorian, S. S., & Lee, S. Y. (1995) · Molecular Carcinogenesis · doi:10.1002/mc.2940140302 · Cited by 21 · see citing works
Flagged first, then by citations
7 of the 72 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The regulation of E2F by pRB-family proteins.
Dyson, N. (1998) · Genes & Development · doi:10.1101/gad.12.15.2245 · Cited by 2,317 · see citing works
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316 · see citing works
Self-citationKastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626 · see citing works
Genetics and biology of pancreatic ductal adenocarcinomaPreprint
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. M., & DePinho, R. A. (2006) · Genes & Development · doi:10.1101/gad.1415606 · Cited by 1,570 · see citing works
Self-citationGenetic Pathways to Primary and Secondary Glioblastoma
Ohgaki, H., & Kleihues, P. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070011 · Cited by 1,487 · see citing works
Miller, A. J., & Mihm, M. C. (2006) · New England Journal of Medicine · doi:10.1056/nejmra052166 · Cited by 1,337 · see citing works
The complexity of p53 modulation: emerging patterns from divergent signalsPreprint
Giaccia, A. J., & Kastan, M. B. (1998) · Genes & Development · doi:10.1101/gad.12.19.2973 · Cited by 1,303 · see citing works
Toxic effects of ultraviolet radiation on the skin
Matsumura, Y., & Ananthaswamy, H. N. (2004) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2003.08.019 · Cited by 1,270 · see citing works
Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization
Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F. (1998) · Genes & Development · doi:10.1101/gad.12.15.2424 · Cited by 1,245 · see citing works
Mayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230 · see citing works
Malignant glioma: genetics and biology of a grave matterPreprint
Maher, E. A., Furnari, F. B., Bachoo, R. M., Rowitch, D. H., Louis, D. N., Cavenee, W. K., & DePinho, R. A. (2001) · Genes & Development · doi:10.1101/gad.891601 · Cited by 1,220 · see citing works
Self-citationThe Pezcoller lecture: cancer cell cycles revisited.
Sherr, C. J. (2000) · PubMed · Cited by 1,193 · see citing works
Stott, F. J., Bates, S., James, M. C., McConnell, B. B., Starborg, M., Brookes, S., Palmero, I., Ryan, K. M., Hara, E., Vousden, K. H., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.5001 · Cited by 1,165 · see citing works
The Rb/E2F pathway: expanding roles and emerging paradigms
Harbour, J. W., & Dean, D. C. (2000) · Genes & Development · doi:10.1101/gad.813200 · Cited by 1,153 · see citing works
Linking the p53 tumour suppressor pathway to somatic cell reprogramming
Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Belmonte, J. C. I. (2009) · Nature · doi:10.1038/nature08311 · Cited by 1,115 · see citing works
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARFPreprint
Jacobs, J. J. L., Scheijen, B., Voncken, J. W., Kieboom, K., Berns, A. J. M., & van Lohuizen, M. (1999) · Genes & Development · doi:10.1101/gad.13.20.2678 · Cited by 1,060 · see citing works
Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · see citing works
Self-citationThe MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982 · see citing works
p53 and Human Cancer: The First Ten Thousand Mutations
Hainaut, P. L., & Hollstein, M. C. (1999) · Advances in cancer research · doi:10.1016/s0065-230x(08)60785-x · Cited by 980 · see citing works
Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · see citing works
Self-citationHER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation
Zhou, B. P., Liao, Y., Xia, W., Zou, Y., Spohn, B., & Hung, M.-C. (2001) · Nature Cell Biology · doi:10.1038/ncb1101-973 · Cited by 951 · see citing works
Nucleolar Arf sequesters Mdm2 and activates p53
Weber, J. D., Taylor, L. J., Roussel, M. F., Sherr, C. J., & Bar-Sagi, D. (1999) · Nature Cell Biology · doi:10.1038/8991 · Cited by 940 · see citing works
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
Nevins, J. R. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.7.699 · Cited by 920 · see citing works
The p16INK4a/CDKN2A tumor suppressor and its relatives
Ruas, M., & Peters, G. (1998) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(98)00017-1 · Cited by 911 · see citing works
Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2
Kamijo, T., Weber, J. D., Zambetti, G., Zindy, F., Roussel, M. F., & Sherr, C. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8292 · Cited by 899 · see citing works
Broad targeting of resistance to apoptosis in cancer
Mohammad, R. M., Muqbil, I., Lowe, L. J., Yedjou, C. G., Hsu, H.-Y., Lin, L., Siegelin, M. D., Fimognari, C., Kumar, N. B., Dou, Q. P., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.03.001 · Cited by 876 · see citing works
Jiang, Y.-H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., & Beaudet, A. L. (1998) · Neuron · doi:10.1016/s0896-6273(00)80596-6 · Cited by 852 · see citing works
Senescence of human fibroblasts induced by oncogenic Raf
Zhu, J., Woods, D., McMahon, M., & Bishop, J. M. (1998) · Genes & Development · doi:10.1101/gad.12.19.2997 · Cited by 826 · see citing works
Telomeres and telomerase in cancer
Artandi, S. E., & DePinho, R. A. (2010) · Carcinogenesis · doi:10.1093/carcin/bgp268 · Cited by 823 · see citing works
Self-citationDisruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis
Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J., & Cleveland, J. L. (1999) · Genes & Development · doi:10.1101/gad.13.20.2658 · Cited by 819 · see citing works
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798 · see citing works
Self-citationRegulation ofp53downstream genes
El‐Deiry, W. S. (1998) · Seminars in Cancer Biology · doi:10.1006/scbi.1998.0097 · Cited by 797 · see citing works
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53
Honda, R., & Yasuda, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.1.22 · Cited by 724 · see citing works
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
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
“The ability of Mdm2 to ubiquinate p53 is negatively regulated by ARF (Pomerantz et al. 1998; Honda and Yasuda 1999; Zhang and Xiong 1999; Fang et al. 2000), suggesting that modifications affecting ARF binding might also modulate Mdm2 function.”
BackgroundInfluentialTumor surveillance via the ARF–p53 pathwayPreprint
Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.19.2984 · Cited by 716 · see citing works
Cyclins and cell cycle checkpoints.
Johnson, D. G., & Walker, C. (1999) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.295 · Cited by 789 · see citing works
The complexity of p53 stabilization and activation
Lavin, M. F., & Gueven, N. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401925 · Cited by 701 · see citing works
Apaf-1 and Caspase-9 in p53-Dependent Apoptosis and Tumor Inhibition
Soengas, M. S., Alarcon, R. M., Yoshida, H., J., A., Giaccia, Hakem, R., Mak, T. W., & Lowe, S. W. (1999) · Science · doi:10.1126/science.284.5411.156 · Cited by 660 · 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
MDM2 — master regulator of the p53 tumor suppressor protein
Momand, J., Wu, H.-H., & Dasgupta, G. (2000) · Gene · doi:10.1016/s0378-1119(99)00487-4 · Cited by 641 · see citing works
SUMO‐1 modification activates the transcriptional response of p53
Rodríguez, M. S., Desterro, J. M. P., Laı́n, S., Midgley, C., Lane, D. P., & Hay, R. T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.22.6455 · Cited by 639 · see citing works
Regulation of HDM2 activity by the ribosomal protein L11
Lohrum, M. A. E., Ludwig, R. L., Kubbutat, M. H. G., Hanlon, M., & Vousden, K. H. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00134-x · Cited by 626 · see citing works
Prives, C. (1998) · Cell · doi:10.1016/s0092-8674(00)81774-2 · Cited by 623 · see citing works
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109745200 · Cited by 617 · 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
E1A signaling to p53 involves the p19ARFtumor suppressorPreprint
de Stanchina, E., McCurrach, M. E., Zindy, F., Shieh, S.-Y., Ferbeyre, G., Samuelson, A. V., Prives, C. L., Roussel, M. F., Sherr, C. J., & Lowe, S. W. (1998) · Genes & Development · doi:10.1101/gad.12.15.2434 · Cited by 607 · see citing works
Divorcing ARF and p53: an unsettled case
Sherr, C. J. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1954 · Cited by 595 · see citing works
Primary and secondary glioblastomas: From concept to clinical diagnosis
Kleihues, P., & Ohgaki, H. (1999) · Neuro-Oncology · doi:10.1093/neuonc/1.1.44 · Cited by 595 · see citing works
Genetic and biological hallmarks of colorectal cancerPreprint
Li, J., Ma, X., Chakravarti, D., Shalapour, S., & DePinho, R. A. (2021) · Genes & Development · doi:10.1101/gad.348226.120 · Cited by 588 · see citing works
Self-citationp300/CBP‐mediated p53 acetylation is commonly induced by p53‐activating agents and inhibited by MDM2
Ito, A., Lai, C.-H., Zhao, X., Saito, S., Hamilton, M. H., Appella, E., & Yao, T. (2001) · The EMBO Journal · doi:10.1093/emboj/20.6.1331 · Cited by 582 · see citing works
Generation of oscillations by the p53-Mdm2 feedback loop: A theoretical and experimental study
Bar‐Or, R. L., Maya, R. B.-Y., Segel, L. A., Alon, U., Levine, A. J., & Oren, M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.210171597 · Cited by 579 · see citing works
Bardeesy, N. M., Aguirre, A. J., Chu, G. C., Cheng, K., Lopez, L. V., Hezel, A. F., Feng, B., Brennan, C. W., Weissleder, R., Mahmood, U., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601273103 · Cited by 575 · see citing works
Self-citationMDM2–HDAC1-mediated deacetylation of p53 is required for its degradation
Ito, A., Kawaguchi, Y., Lai, C., Kovacs, J. J., Higashimoto, Y., Appella, E., & Yao, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf616 · Cited by 570 · see citing works
Ishii, N., Maier, D., Merlo, A., Tada, M., Sawamura, Y., Diserens, A., & Van Meir, E. G. (1999) · Brain Pathology · doi:10.1111/j.1750-3639.1999.tb00536.x · Cited by 569 · see citing works
Regulation of the p53 Tumor Suppressor Protein
Oren, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.51.36031 · Cited by 561 · see citing works
Zhang, Y., Wolf, G. W., Bhat, K., Jin, A., Allio, T., Burkhart, W., & Xiong, Y. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.23.8902-8912.2003 · Cited by 556 · see citing works
Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems
Kohn, K. W. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.8.2703 · Cited by 550 · see citing works
P19 ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2
Tao, W., & Levine, A. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.12.6937 · Cited by 539 · see citing works
ARF-BP1/Mule Is a Critical Mediator of the ARF Tumor Suppressor
Chen, D., Kon, N., Li, M., Zhang, W., Qin, J., & Gu, W. J. (2005) · Cell · doi:10.1016/j.cell.2005.03.037 · Cited by 539 · see citing works
The INK4A/ARF locus and its two gene products.
Sharpless, N. E., & DePinho, R. A. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80004-5 · Cited by 533 · see citing works
Self-citationShackelford, R. E., Kaufmann, W. K., & Paules, R. S. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00224-0 · Cited by 520 · see citing works
Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy
Choi, S., & Myers, J. N. (2008) · Journal of Dental Research · doi:10.1177/154405910808700104 · Cited by 514 · see citing works
Malignant melanoma: genetics and therapeutics in the genomic eraPreprint
Chin, L., Garraway, L. A., & Fisher, D. E. (2006) · Genes & Development · doi:10.1101/gad.1437206 · Cited by 509 · see citing works
Self-citationRb function in cell-cycle regulation and apoptosis
Harbour, J. W., & Dean, D. C. (2000) · Nature Cell Biology · doi:10.1038/35008695 · Cited by 504 · see citing works
Geographical Variation in the Penetrance of CDKN2A Mutations for Melanoma
Bishop, D. T. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.12.894 · Cited by 503 · see citing works
Melanoma: from mutations to medicine
Tsao, H., Chin, L., Garraway, L. A., & Fisher, D. E. (2012) · Genes & Development · doi:10.1101/gad.191999.112 · Cited by 496 · see citing works
Self-citationFrank, K. M., Sharpless, N. E., Gao, Y., Sekiguchi, J., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J. W., DePinho, R. A., & Alt, F. W. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80264-6 · Cited by 492 · see citing works
Self-citationDifferent telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482 · see citing works
Telomeres, stem cells, senescence, and cancer
Sharpless, N. E., & DePinho, R. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20761 · Cited by 479 · see citing works
Self-citationEsteller, M., Tórtola, S., Toyota, M., Capellá, G., Peinado, M. A., Baylin, S. B., & Herman, J. G. (2000) · PubMed · Cited by 464 · 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
INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R., & Lowe, S. W. (1999) · Genes & Development · doi:10.1101/gad.13.20.2670 · Cited by 458 · see citing works
The Developmental Biology of Brain Tumors
Wechsler‐Reya, R. J., & Scott, M. P. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.385 · Cited by 458 · see citing works
Gliomagenesis: genetic alterations and mouse models
Holland, E. C. (2001) · Nature Reviews Genetics · doi:10.1038/35052535 · Cited by 453 · see citing works
Regulation of p53 function and stability by phosphorylation.
Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1751 · Cited by 452 · see citing works
Genetic alterations and signaling pathways in the evolution of gliomas
Ohgaki, H., & Kleihues, P. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01308.x · Cited by 452 · see citing works
INK4a/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
Itahana, K., Bhat, K., Jin, A., Itahana, Y., Hawke, D. H., Kobayashi, R., & Zhang, Y. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00431-3 · Cited by 431 · see citing works
Goldstein, A. M., Chan, M., Harland, M., Gillanders, E. M., Hayward, N. K., Avril, M.-F., Azizi, E., Bianchi-Scarra, G., Bishop, D. T., Bressac-de Paillerets, B., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0494 · Cited by 426 · see citing works
Implications of Genetic and Epigenetic Alterations of CDKN2A (p16 INK4a ) in Cancer
Zhao, R., Choi, B. Y., Lee, M.-H., Bode, A. M., & Dong, Z. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.04.017 · Cited by 425 · see citing works
Yin Yang 1 Is a Negative Regulator of p53
Sui, G., Affar, E. B., Shi, Y. G., Brignone, C., Wall, N. R., Yin, P., Donohoe, M., Luke, M. P.-S., Calvo, D., Grossman, S. R., et al. (2004) · Cell · doi:10.1016/j.cell.2004.06.004 · Cited by 423 · see citing works
p53-Dependent apoptosis pathways
Shen, Y., & White, E. (2001) · Advances in cancer research · doi:10.1016/s0065-230x(01)82002-9 · Cited by 415 · see citing works
Lipkowitz, S., & Weissman, A. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3120 · Cited by 415 · see citing works
p300/MDM2 complexes participate in MDM2-mediated p53 degradation
Grossman, S. R., Perez, M., Kung, A. L., Joseph, M., Mansur, C., Xiao, Z.-X., Kumar, S., Howley, P. M., & Livingston, D. M. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80140-9 · Cited by 414 · see citing works
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
Ashcroft, M. A., & Vousden, K. H. (1999) · Oncogene · doi:10.1038/sj.onc.1203012 · Cited by 407 · see citing works
The retinoblastoma gene family in differentiation and development
Lipinski, M. M., & Jacks, T. (1999) · Oncogene · doi:10.1038/sj.onc.1203244 · Cited by 404 · see citing works
Lang, F. F., Bruner, J. M., Fuller, G. N., Aldape, K., Prados, M. D., Chang, S. M., Berger, M. S., McDermott, M. W., Kunwar, S. M., Junck, L., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.21.13.2508 · Cited by 396 · see citing works
Dimri, G. P., Itahana, K., Acosta, M., & Campisi, J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.1.273-285.2000 · Cited by 393 · see citing works
TP53 Mutations in Nonsmall Cell Lung Cancer
Mogi, A., & Kuwano, H. (2011) · BioMed Research International · doi:10.1155/2011/583929 · Cited by 392 · see citing works
NF-κB and cell-cycle regulation: the cyclin connection
JOYCE, D., ALBANESE, C., Steer, J. H., Fu, M., Bouzahzah, B., & Pestell, R. G. (2001) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(00)00018-6 · Cited by 390 · see citing works
Culmsee, C., & Mattson, M. P. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.149 · 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
Physical and Functional Interactions of the Arf Tumor Suppressor Protein with Nucleophosmin/B23
Bertwistle, D., Sugimoto, M., & Sherr, C. J. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.985-996.2004 · Cited by 380 · see citing works
Pestell, R. G., Albanese, C., Reutens, A. T., Segall, J. E., Lee, R. J., & Arnold, A. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.4.0373 · Cited by 376 · see citing works
Tsai, K. Y., Hu, Y., Macleod, K. F., Crowley, D., Yamasaki, L., & Jacks, T. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80274-9 · Cited by 372 · see citing works
- Authors
- Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., Cordon-Cardo, C., & DePinho, R. A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- DePinho, Ronald A
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1998-03
- Volume
- 92
- Issue
- 6
- Pages
- 713-723
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2039463309
- Cited by
- 1,521
- References
- 72
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 6 · 2023: 23 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 16 · 2018: 12 · 2017: 24 · 2016: 27 · 2015: 32 · 2014: 44 · 2013: 44 · 2012: 47
- FWCI
- 64.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 47179, CA 47538, CADK97650, P01CA047179)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p19ARF, INK4A, MDM2, p53, tumor suppression, protein-protein interaction, p53 degradation, p53 transactivation, oncogenic transformation, Rb pathway, viral oncoproteins, dominant-negative mutant
- MeSH terms
- Animals, Biotin, Cell Line, Deoxyuracil Nucleotides, Lens, Crystalline, Neoplasm Proteins, Nuclear Proteins, Osteoblasts, Proteins, Proto-Oncogene Proteins, Staining and Labeling, Transformation, Genetic, Tumor Suppressor Protein p53, Retinoblastoma Protein, Apoptosis, Genes, p16, Tumor Suppressor Protein p14ARF, Mice, Proto-Oncogene Proteins c-mdm2, DNA Fragmentation
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