The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Open accessAbstract
p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. In this study, we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation of p53. Both Akt expression and serum treatment induced phosphorylation of Mdm2 at Ser186. Akt-mediated phosphorylation of Mdm2 at Ser186 had little effect on the subcellular localization of Mdm2. However, both Akt expression and serum treatment increased Mdm2 ubiquitination of p53. The serum-induced increase in p53 ubiquitination was blocked by LY294002, a phosphatidylinositol 3-OH-kinase inhibitor. Moreover, when Ser186 was replaced by Ala, Mdm2 became resistant to Akt enhancement of p53 ubiquitination and degradation. Collectively, these results suggest that Akt enhances the ubiquitination-promoting function of Mdm2 by phosphorylation of Ser186, which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation, and tumorigenesis.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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?
In the citing paper
“We and other groups (58) did not observe significant changes in the subcellular localization of Mdm2 when PKB was activated by a variety of stimuli (data not shown).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [58]
Citations
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
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., & Greenberg, M. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80405-5 · Cited by 5,689
Self-citationAkt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., & Greenberg, M. E. (1999) · Cell · doi:10.1016/s0092-8674(00)80595-4 · Cited by 5,594
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244
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
Cellular survival: a play in three Akts
Datta, S. R., Brunet, A., & Greenberg, M. E. (1999) · Genes & Development · doi:10.1101/gad.13.22.2905 · Cited by 4,216
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
Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN
Stambolic, V., Suzuki, A., de la Pompa, J. L., Brothers, G. M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J. M., Siderovski, D. P., & Mak, T. W. (1998) · Cell · doi:10.1016/s0092-8674(00)81780-8 · Cited by 2,551
Regulation of Cell Death Protease Caspase-9 by Phosphorylation
Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E., Frisch, S., & Reed, J. C. (1998) · Science · doi:10.1126/science.282.5392.1318 · Cited by 2,481
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951
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
NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase
Nidai Ozes, O., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B. (1999) · Nature · doi:10.1038/43466 · Cited by 1,832
Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt
Peso, L. D., González-Garcı́a, M., Page, C., Herrera, R., & Nuñez, G. (1997) · Science · doi:10.1126/science.278.5338.687 · Cited by 1,797
The PI3K‒PDK1 connection: more than just a road to PKB
Vanhaesebroeck, B., & Alessi, D. R. (2000) · Biochemical Journal · doi:10.1042/bj3460561 · Cited by 1,649
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626
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
NF-κB is a target of AKT in anti-apoptotic PDGF signalling
Romashkova, J. A., & Makarov, S. S. (1999) · Nature · doi:10.1038/43474 · Cited by 1,517
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
Mayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230
Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB
Kauffmann-Zeh, A., Rodriguez‐Viciana, P., Ulrich, E., Gilbert, C. S., Coffer, P. J., Downward, J., & Evan, G. I. (1997) · Nature · doi:10.1038/385544a0 · Cited by 1,144
Rodriguez‐Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A. J., & Downward, J. (1997) · Cell · doi:10.1016/s0092-8674(00)80226-3 · Cited by 1,060
Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway
Pap, M., & Cooper, G. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.32.19929 · Cited by 1,046
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
Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., & Lowe, S. W. (1998) · Genes & Development · doi:10.1101/gad.12.19.3008 · Cited by 945
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
Oncogenic Forms of p53 Inhibit p53-Regulated Gene Expression
Kern, S. E., Pietenpol, J., Thiagalingam, S., Seymour, A., Kinzler, K. W., & Vogelstein, B. (1992) · Science · doi:10.1126/science.1589764 · Cited by 940
A Retroviral Oncogene, akt , Encoding a Serine-Threonine Kinase Containing an SH2-Like Region
Bellacosa, A., Testa, J. R., Staal, S. P., & Tsichlis, P. N. (1991) · Science · doi:10.1126/science.1833819 · Cited by 939
Vousden, K. H. (2000) · Cell · doi:10.1016/s0092-8674(00)00171-9 · Cited by 785
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 731
Tumor surveillance via the ARF–p53 pathwayPreprint
Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.19.2984 · Cited by 718
Mapping 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 700
Akt/Protein Kinase B Inhibits Cell Death by Preventing the Release of Cytochrome c from Mitochondria
Kennedy, S. G., Kandel, E., Cross, T. K., & Hay, N. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.8.5800 · Cited by 653
p19ARF links the tumour suppressor p53 to Ras
Palmero, I., Pantoja, C., & Serrano, M. (1998) · Nature · doi:10.1038/25870 · Cited by 619
Roth, J., Dobbelstein, M., Freedman, D. A., Shenk, T., & Levine, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.554 · Cited by 610
Jones, P. F., Jakubowicz, T., Pitossi, F. J., Maurer, F., & Hemmings, B. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.10.4171 · Cited by 532
Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level
Zhou, H., Li, X., Meinkoth, J. L., & Pittman, R. N. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.151.3.483 · Cited by 514
Coffer, P. J., & Woodgett, J. R. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb16305.x · Cited by 489
Peptide and Protein Library Screening Defines Optimal Substrate Motifs for AKT/PKB
Obata, T., Yaffe, M. B., Leparc, G., Piro, E. T., Maegawa, H., Kashiwagi, A., Kikkawa, R., & Cantley, L. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005497200 · Cited by 389
Self-citationFukuda, M., Gotoh, Y., & Nishida, E. (1997) · The EMBO Journal · doi:10.1093/emboj/16.8.1901 · Cited by 385
Self-citationThe MDM2 RING-finger domain is required to promote p53 nuclear export
Geyer, R. K., Yu, Z. K., & Maki, C. G. (2000) · Nature Cell Biology · doi:10.1038/35023507 · Cited by 361
The ras Oncogenes Increase the Intrinsic Resistance of NIH 3T3 Cells to Ionizing Radiation
Sklar, M. D. (1988) · Science · doi:10.1126/science.3277276 · Cited by 358
Opposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357
Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53
Tao, W., & Levine, A. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3077 · Cited by 355
An intact HDM2 RING-finger domain is required for nuclear exclusion of p53
Boyd, S. D., Tsai, K. Y., & Jacks, T. (2000) · Nature Cell Biology · doi:10.1038/35023500 · Cited by 334
The Protooncogene TCL1 Is an Akt Kinase Coactivator
Laine, J. T., Künstle, G., Obata, T., Ma, S., & Noguchi, M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00039-3 · Cited by 327
Self-citationWoods, D. B., & Vousden, K. H. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5141 · Cited by 323
Kohn, A. D., Barthel, A., Kovacina, K. S., Boge, A., Wallach, B. J., Summers, S. A., Birnbaum, M. J., Scott, P., Lawrence, J. C., & Roth, R. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11937 · Cited by 304
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
(1997) · PubMed · Cited by 243
Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N., & Tohyama, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008552200 · Cited by 242
Mdm2 association with p53 targets its ubiquitination
Fuchs, S. Y., Adler, V., Buschmann, T., Wu, X., & Ronai, Z. A. (1998) · Oncogene · doi:10.1038/sj.onc.1202200 · Cited by 235
Kobet, E., Zeng, X., Zhu, Y., Keller, D., & Lu, H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.23.12547 · Cited by 193
Akt phosphorylates and regulates the orphan nuclear receptor Nur77
Pekarsky, Y., Hallas, C., Palamarchuk, A., Koval, A. P., Bullrich, F., Hirata, Y., Bichi, R., Letofsky, J., & Croce, C. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051003198 · Cited by 177
Akt Inhibits the Orphan Nuclear Receptor Nur77 and T-cell Apoptosis
Masuyama, N., Oishi, K., Mori, Y., Ueno, T., Takahama, Y., & Gotoh, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105431200 · Cited by 151
Self-citationSabbatini, P., & McCormick, F. P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24263 · Cited by 141
Loss of PTEN expression leading to high Akt activation in human multiple myelomas
Hyun, T. S., Yam, A., Pece, S., Xie, X., Zhang, J., Miki, T., Gutkind, J. S., & Li, W. (2000) · Blood · doi:10.1182/blood.v96.10.3560 · Cited by 127
McFall, A., ülkuü, A., Lambert, Q. T., Kusa, A., Rogers-Graham, K., & Der, C. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.16.5488-5499.2001 · Cited by 120
Wadgaonkar, R., & Collins, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.20.13760 · Cited by 97
Cyclin A-CDK Phosphorylation Regulates MDM2 Protein Interactions
Zhang, T., & Prives, C. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011326200 · Cited by 70
Hay, T., & Meek, D. W. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01850-0 · Cited by 62
Flagged first, then by citations
Research works printed but not linked: 4
- Chen, 1993, Mol. Cell. Biol., 13, 4107
- Mayo, 1997, Cancer Res., 57, 5013
- Bellacosa, 1991, Science, 254, 274
- Kern, 1992, Science, 256, 827, 10.1126/science.256.5058.827 · DOI
Cited by
Sorted by citations
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Wee, P., & Wang, Z. (2017) · Cancers · doi:10.3390/cancers9050052 · Cited by 2,027
Growing roles for the mTOR pathway
Sarbassov, D. D., Ali, S. M., & Sabatini, D. M. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.09.009 · Cited by 1,590
“Akt/PKB is a key component of the insulin/PI3K signaling pathway and modulates cell survival and proliferation through downstream substrates such as the FOXO class of transcription factors (reviewed in [42]) and the p53-regulator mdm2 [43,44].”
BackgroundPI3K/Akt and apoptosis: size matters
Franke, T. F., Hornik, C., Segev, L., Shostak, G. A., & Sugimoto, C. (2003) · Oncogene · doi:10.1038/sj.onc.1207115 · Cited by 1,195
“Two alternative mechanisms of Aktdependent regulation of Mdm2/HDM2 have been described, and they include the induction of Mdm2 nuclear import (Mayo and Donner, 2001) or the regulation of Mdm2/HDM2-ubiquitin ligase enzymatic activity (Zhou et al., 2001b; Ashcroft et al., 2002; Ogawara et al., 2002).”
BackgroundDecision making by p53: life, death and cancer
Oren, M. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401183 · Cited by 1,085
PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside
Alzahrani, A. S. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.009 · Cited by 1,056
Metadata
- Authors
- Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y.
- Affiliations
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Tokushima University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Gotoh, Yukiko
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 24
- Pages
- 21843-21850
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2027217537
- Semantic Scholar
- bca1d1791eb8e2056d050c2ab2b91129d0d06de7
- Cited by
- 617
- References
- 60
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 11 · 2023: 19 · 2022: 19 · 2021: 34 · 2020: 29 · 2019: 28 · 2018: 33 · 2017: 31 · 2016: 36 · 2015: 28 · 2014: 35 · 2013: 43 · 2012: 29
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Akt, MDM2, p53, ubiquitination, protein degradation, PI3K/Akt signaling, p53 stabilization, LY294002, carcinogenesis, apoptosis
- MeSH terms
- Cell Survival, Chromones, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Microscopy, Fluorescence, Morpholines, Nuclear Proteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, RNA, Messenger, Serine, Subcellular Fractions, Time Factors, Tumor Cells, Cultured, Blotting, Western, Retroviridae Proteins, Oncogenic, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin, Proto-Oncogene Proteins c-akt, Oncogene Protein v-akt, 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
