ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways
Open accessAbstract
The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The functional consequence of ARF-regulated p53 levels via MDM2 proteolysis is evidenced by the ability of ectopically expressed ARF to restore a p53-imposed G1 cell cycle arrest that is otherwise abrogated by MDM2. Thus, deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARF-MDM2-p53 pathways.
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 [21]
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 [49]
ARF directly binds Mdm2 and holds it away from p53 in the nucleolus or nucleus.
“Oncogenic activity transcriptionally up regulates and post-translationally stabilizes ARF, which directly binds Mdm2 and holds Mdm2 away from p53 either in the nucleolus or the nucleus (Figure 1) (Chen, et al., 2010; Eischen, et al., 1999; Llanos, et al., 2001; Weber, et al., 1999; Zhang, et al., 1998; Zindy, et al., 1998).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Zhang, et al., 1998
The role of ATM in p53 response is well established, but the significance of Chk2 is debated.
“Although a role of ATM in p53 response is well established, the significance of Chk2 is still a matter of debate.”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Zhang et al, 1998
Different conclusions have emerged from work with Chk2-null mice, Chk2-null HCT116 cells, and Chk2 small interfering RNA.
“Studies using Chk2-null mice, Chk2-null HCT116 cells, and Chk2 siRNA resulted in different conclusions (Zhang et al, 1998;Chehab et al, 2000;Shieh et al, 2000;Ahn et al, 2003; Jallepalli et al, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Zhang et al, 1998
Cites
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
A novel genetic system to detect protein–protein interactions
Fields, S., & Song, O.-K. (1989) · Nature · doi:10.1038/340245a0 · Cited by 6,152 · 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 E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990) · Cell · doi:10.1016/0092-8674(90)90409-8 · Cited by 3,995 · see citing works
p21 is a universal inhibitor of cyclin kinases
Xiong, Y., Hannon, G., Zhang, H., Casso, D., Kobayashi, R., & Beach, D. (1993) · Nature · doi:10.1038/366701a0 · Cited by 3,691 · see citing works
Self-citationA 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
Inhibitors of mammalian G1 cyclin-dependent kinases.Preprint
Sherr, C. J., & Roberts, J. M. (1995) · Genes & Development · doi:10.1101/gad.9.10.1149 · Cited by 3,222 · 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
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
Scheffner, M., Huibregtse, J. M., Vierstra, R. D., & Howley, P. M. (1993) · Cell · doi:10.1016/0092-8674(93)90384-3 · Cited by 2,387 · 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
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100 · see citing works
Cyclins and cancer II: Cyclin D and CDK inhibitors come of age
Hunter, T. R., & Pines, J. (1994) · Cell · doi:10.1016/0092-8674(94)90543-6 · Cited by 2,094 · 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
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801 · 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
Tumor 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
Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81400-2 · Cited by 1,521 · 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
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · see citing works
mdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · 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
(1993) · Genes & Development · doi:10.1101/gad.7.3.331 · Cited by 1,264 · see citing works
Functional interactions of the retinoblastoma protein with mammalian D-type cyclins
Ewen, M. E., Sluss, H. K., Sherr, C. J., Matsushime, H., Kato, J.-Y., & Livingston, D. M. (1993) · Cell · doi:10.1016/0092-8674(93)90136-e · Cited by 1,010 · see citing works
Huibregtse, J. M., Scheffner, M., & Howley, P. M. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb04990.x · Cited by 879 · see citing works
Guan, K., Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O'Keefe, C., Matera, A. G., & Xiong, Y. (1994) · Genes & Development · doi:10.1101/gad.8.24.2939 · Cited by 707 · see citing works
Self-citationMapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 689 · see citing works
In vivo ubiquitination and proteasome-mediated degradation of p53(1).
Maki, C. G., Huibregtse, J. M., & Howley, P. M. (1996) · PubMed · Cited by 645 · see citing works
p53 Mutation and MDM2 amplification in human soft tissue sarcomas.
Leach, F. S., Tokino, T., Meltzer, P. S., Burrell, M., Oliner, J., Smith, S., HILL, D. E., Sidransky, D., Kinzler, K. W., & Vogelstein, B. (1993) · PubMed · Cited by 533 · see citing works
Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.Preprint
Xiong, Y., Zhang, H., & Beach, D. (1993) · Genes & Development · doi:10.1101/gad.7.8.1572 · Cited by 507 · 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
Complex structure and regulation of the P16 (MTS1) locus.
Stone, S., Jiang, P., Dayananth, P., Tavtigian, S. V., Katcher, H. L., Parry, D., Peters, G., & Kamb, A. (1995) · PubMed · Cited by 383 · see citing works
Parry, D., Bates, S., Mann, D. J., & Peters, G. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07026.x · Cited by 354 · see citing works
mdm-2 Inhibits the G1 Arrest and Apoptosis Functions of the p53 Tumor Suppressor Protein
Chen, J., Wu, X., Lin, J., & Levine, A. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2445 · Cited by 350 · see citing works
Mao, L., Merlo, A. U., Bedi, G. C., Shapiro, G. I., Edwards, C. D., Rollins, B. J., & Sidransky, D. (1995) · PubMed · Cited by 329 · 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
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
Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.
Chen, C. Y., Oliner, J., Zhan, Q., Fornace, A. J., Vogelstein, B., & Kastan, M. B. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.7.2684 · Cited by 270 · 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
Chromosome 11q13 abnormalities in human cancer.
Lammie, G. A., & Peters, G. B. (1991) · PubMed · Cited by 154 · see citing works
Functional p53 protein in human papillomavirus-positive cancer cells.
Butz, K., Shahabeddin, L., Geisen, C., et al. (1995) · PubMed · Cited by 148 · see citing works
A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies.
Duro, D., Bernard, O., Della-Valle, V., Berger, R., & Larsen, C. (1995) · PubMed · Cited by 130 · see citing works
Familial Tumor Syndrome Associated With a Germline Nonfunctional p16INK4a Allele
Yarbrough, W. G., Aprelikova, O. N., Pei, H., et al. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.20.1489 · Cited by 72 · see citing works
Self-citationImmunoprecipitation and Immunoblotting in Cell Cycle Studies
Jenkins, C. W., & Xiong, Y. (1996) · Springer eBooks · doi:10.1007/978-3-642-57783-3_22 · Cited by 26 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Genomic instability — an evolving hallmark of cancer
Negrini, S., Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2858 · Cited by 2,397 · see citing works
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
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Comparative Genomics of the Eukaryotes
Rubin, G. M., Yandell, M. D., Wortman, J. R., Gabor, G. L., Miklos, Nelson, C. R., Hariharan, I. K., Fortini, M. E., Li, P. W., Apweiler, R., et al. (2000) · Science · doi:10.1126/science.287.5461.2204 · Cited by 1,698 · see citing works
Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81400-2 · Cited by 1,521 · 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
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
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
The MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982 · see citing works
HER-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
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
Disruption 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
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
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
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
Mutational processes shape the landscape of TP53 mutations in human cancer
Giacomelli, A. O., Yang, X., Lintner, R. E., McFarland, J. M., Duby, M., Kim, J., Howard, T. P., Takeda, D. Y., Ly, S. H., Kim, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0204-y · Cited by 556 · 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
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
MDM2–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
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
twist is a potential oncogene that inhibits apoptosis
Maestro, R., Tos, A. P. D., Hamamori, Y., Krasnokutsky, S., Sartorelli, V., Kedes, L., Doglioni, C., Beach, D. H., & Hannon, G. J. (1999) · Genes & Development · doi:10.1101/gad.13.17.2207 · Cited by 516 · 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
Different 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
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
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
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
NUMB 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
A p53 Amino-Terminal Nuclear Export Signal Inhibited by DNA Damage-Induced Phosphorylation
Zhang, Y., & Xiong, Y. (2001) · Science · doi:10.1126/science.1058637 · Cited by 378 · see citing works
Self-citationTsai, 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
Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse
Greenberg, R. A., Chin, L., Femino, A., Lee, K.-H., Gottlieb, G. J., Singer, R. H., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80761-8 · Cited by 367 · see citing works
Melk, A., Schmidt, B. M. W., Takeuchi, O., Sawitzki, B., Rayner, D. C., & Halloran, P. F. (2004) · Kidney International · doi:10.1111/j.1523-1755.2004.00438.x · Cited by 362 · see citing works
Robertson, K. D., & Jones, P. A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.11.6457 · Cited by 352 · see citing works
Polycomb 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
Novel Insights into Mesothelioma Biology and Implications for Therapy
Yap, T. A., Aerts, J. G., Popat, S., & Fennell, D. A. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.42 · Cited by 324 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricalà, C., & O'Toole, K. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5157-5172.2002 · Cited by 338 · see citing works
MDM2 suppresses p73 function without promoting p73 degradation
Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Oren, M., Chen, J., & Lu, H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3257 · Cited by 334 · see citing works
MDM2 interacts with MDMX through their RING finger domains
Tanimura, S., Ohtsuka, S., Mitsui, K., Shirouzu, K., Yoshimura, A., & Ohtsubo, M. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00254-9 · Cited by 324 · see citing works
MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
Sdek, P., Ying, H., Chang, D. L. F., Qiu, W., Zheng, H., Touitou, R., Allday, M. J., & Jim Xiao, Z.-X. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.017 · Cited by 288 · see citing works
Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286 · see citing works
ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600812 · Cited by 260 · see citing works
Genetic pathways to glioblastomas
Ohgaki, H. (2005) · Neuropathology · doi:10.1111/j.1440-1789.2004.00600.x · Cited by 235 · 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
Cyclin G Recruits PP2A to Dephosphorylate Mdm2
Okamoto, K., Li, H., Jensen, M. R., Zhang, T., Taya, Y., Thorgeirsson, S. S., & Prives, C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00504-x · Cited by 215 · see citing works
MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation
Jin, Y., Lee, H., Zeng, S. X., Dai, M., & Lu, H. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg600 · Cited by 206 · see citing works
Pantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201 · see citing works
Genetic and Epigenetic Changes in Human Epithelial Cells Immortalized by Telomerase
Farwell, D. G., Shera, K. A., Koop, J. I., Bonnet, G. A., Matthews, C. P., Reuther, G. W., Coltrera, M. D., McDougall, J. K., & Klingelhutz, A. J. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65025-0 · Cited by 196 · see citing works
Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo
Xirodimas, D., Saville, M. K., Edling, C., Lane, D. P., & Laín, S. (2001) · Oncogene · doi:10.1038/sj.onc.1204656 · Cited by 169 · see citing works
Rane, S. G., Cosenza, S. C., Mettus, R. V., & Reddy, E. P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.644-656.2002 · Cited by 167 · see citing works
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
Inactivation of the p53-homologue p73 by the mdm2-oncoprotein
Dobbelstein, M., Wienzek, S., König, C., & Roth, J. (1999) · Oncogene · doi:10.1038/sj.onc.1202512 · Cited by 161 · see citing works
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
Suppression 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
Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110492200 · Cited by 154 · see citing works
DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation
Blattner, C., Tobiasch, E., Litfen, M., Rahmsdorf, H. J., & Herrlich, P. (1999) · Oncogene · doi:10.1038/sj.onc.1202480 · Cited by 151 · see citing works
Inoue, K., Roussel, M. F., & Sherr, C. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3993 · Cited by 144 · see citing works
Ink4a/Arf links senescence and aging
Sharpless, N. E. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.06.025 · Cited by 142 · see citing works
Mdm2 haplo‐insufficiency profoundly inhibits Myc‐induced lymphomagenesis
Alt, J. R., Greiner, T. C., Cleveland, J. L., & Eischen, C. M. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg133 · Cited by 129 · see citing works
Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122 · see citing works
Rowland, B. D., Denissov, S. G., Douma, S., Stunnenberg, H. G., Bernards, R., & Peeper, D. S. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00085-5 · Cited by 120 · see citing works
Huot, T. J., Rowe, J., Harland, M., Drayton, S., Brookes, S., Gooptu, C., Purkis, P., Fried, M., Bataille, V., Hara, E., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.23.8135-8143.2002 · Cited by 107 · see citing works
To clear, or not to clear (senescent cells)? That is the question
Lujambio, A. (2016) · BioEssays · doi:10.1002/bies.201670910 · Cited by 108 · see citing works
Khan, S. H., Moritsugu, J., & Wahl, G. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3266 · Cited by 103 · see citing works
P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2
Xirodimas, D. P., Chisholm, J., Desterro, J. M. S., Lane, D. P., & Hay, R. T. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03310-0 · Cited by 94 · see citing works
The genetics of melanoma: recent advances
Hill, V. K., Gartner, J. J., Samuels, Y., & Goldstein, A. M. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153429 · Cited by 86 · see citing works
Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function.
Nihira, N. T., Ogura, K., Shimizu, K., North, B. J., Zhang, J., Gao, D., Inuzuka, H., & Wei, W. (2017) · Science Signaling · doi:10.1126/scisignal.aai8026 · Cited by 82 · see citing works
The Mdm network and its regulation of p53 activities: a rheostat of cancer risk
Eischen, C. M., & Lozano, G. (2014) · Human Mutation · doi:10.1002/humu.22524 · Cited by 79 · see citing works
Absence of p16 <sup>INK4a</sup> and truncation of ARF tumor suppressors in chickens
Kim, S.-H., Mitchell, M., Fujii, H., Llanos, S., & Peters, G. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0135557100 · Cited by 63 · see citing works
Lewis, J. L., Chinswangwatanakul, W., Zheng, B., Marley, S. B., Nguyen, D. X., Cross, N. C. P., Banerji, L., Glassford, J., Thomas, N. S. B., Goldman, J. M., et al. (2001) · Blood · doi:10.1182/blood.v97.9.2604 · Cited by 53 · see citing works
Khoo, C. M., Carrasco, D. R., Bosenberg, M. W., Paik, J.-H., & DePinho, R. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700093104 · Cited by 52 · see citing works
Sarkar-Agrawal, P., Vergilis, I., Sharpless, N. E., DePinho, R. A., & Runger, T. M. (2004) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djh307 · Cited by 48 · see citing works
Cooperativity of p19ARF, Mdm2, and p53 in murine tumorigenesis
Moore, L., Venkatachalam, S., Vogel, H., Watt, J. C., Wu, C.-L., Steinman, H., Jones, S. N., & Donehower, L. A. (2003) · Oncogene · doi:10.1038/sj.onc.1206985 · Cited by 48 · see citing works
Small molecules that bind the Mdm2 RING stabilize and activate p53
Roxburgh, P., Hock, A. K., Dickens, M. P., Mezna, M., Fischer, P. M., & Vousden, K. H. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs092 · Cited by 43 · see citing works
P53: Stability from the Ubiquitin–Proteasome System and Specific 26S Proteasome Inhibitors
do Patrocinio, A. B., Rodrigues, V., & Guidi Magalhães, L. (2022) · ACS Omega · doi:10.1021/acsomega.1c04726 · Cited by 36 · see citing works
A BDNF-TrkB autocrine loop enhances senescent cell viability
Anerillas, C., Herman, A. B., Munk, R., Garrido, A., Lam, K.-W. G., Payea, M. J., Rossi, M., Tsitsipatis, D., Martindale, J. L., Piao, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33709-8 · Cited by 35 · see citing works
Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis
Lehman, J., & Mayo, L. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131216373 · Cited by 9 · see citing works
- Authors
- Zhang, Y., Xiong, Y., & Yarbrough, W. G.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Xiong, Yue
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1998-03
- Volume
- 92
- Issue
- 6
- Pages
- 725-734
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1983751803
- Cited by
- 1,626
- References
- 47
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 16 · 2023: 27 · 2022: 25 · 2021: 32 · 2020: 39 · 2019: 22 · 2018: 31 · 2017: 39 · 2016: 42 · 2015: 44 · 2014: 57 · 2013: 57 · 2012: 71
- FWCI
- 57.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5k08ca072968-04)
- National Cancer Institute (R01CA065572, R01CA65572, KO8-CA72968)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- ARF, MDM2, p53 stabilization, INK4a/ARF locus, p16INK4a, tumor suppression, MDM2 degradation, protein-protein interaction, G1 cell cycle arrest, cyclin D
- MeSH terms
- Cell Division, Exons, HeLa Cells, Humans, Nuclear Proteins, Protein Binding, Proteins, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Retinoblastoma Protein, Mutagenesis, Gene Deletion, Genes, p16, Tumor Suppressor Protein p14ARF, Proto-Oncogene Proteins c-mdm2
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