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.
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?
We and other groups did not observe significant changes in subcellular localization of Mdm2 when PKB was activated by a variety of stimuli.
“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]
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
Akt 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 6,535 · see citing works
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 · see citing works
Self-citationInhibition 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 · 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
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 · 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
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. J., Frisch, S. M., & Reed, J. C. (1998) · Science · doi:10.1126/science.282.5392.1318 · Cited by 3,118 · see citing works
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 · see citing works
Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt
del Peso, L., González‐García, M., Page, C., Herrera, R., & Núñez, G. (1997) · Science · doi:10.1126/science.278.5338.687 · Cited by 2,213 · see citing works
NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase
Özeş, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B. (1999) · Nature · doi:10.1038/43466 · Cited by 2,175 · see citing works
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 · 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
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 1,847 · see citing works
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 1,632 · 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
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
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
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 1,148 · see citing works
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 1,063 · see citing works
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 · 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
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 · 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
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 · see citing works
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 · see citing works
Vousden, K. H. (2000) · Cell · doi:10.1016/s0092-8674(00)00171-9 · Cited by 785 · 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
Tumor 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
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 689 · see citing works
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 651 · see citing works
p19ARF links the tumour suppressor p53 to Ras
Palmero, I., Pantoja, C., & Serrano, M. (1998) · Nature · doi:10.1038/25870 · Cited by 617 · see citing works
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 · see citing works
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 · see citing works
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 511 · see citing works
Coffer, P. J., & Woodgett, J. R. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb16305.x · Cited by 493 · see citing works
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 388 · see citing works
Self-citationFukuda, M., Gotoh, Y., & Nishida, E. (1997) · The EMBO Journal · doi:10.1093/emboj/16.8.1901 · Cited by 385 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Oncogenic Forms of p53 Inhibit p53-Regulated Gene Expression
Kern, S. E., Pietenpol, J. A., Thiagalingam, S., et al. (1992) · Science · doi:10.1126/science.256.5058.827 · Cited by 342 · see citing works
Kohn, A. D., Barthel, A., Kovacina, K., Boge, A., Wallach, B., Summers, S., Birnbaum, M., Scott, P. H., Lawrence, J., & Roth, R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11937 · Cited by 340 · see citing works
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 · see citing works
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 · see citing works
Self-citationWoods, D. B., & Vousden, K. H. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5141 · Cited by 318 · 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
(1997) · PubMed · Cited by 243 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citationSabbatini, P., & McCormick, F. P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24263 · Cited by 139 · see citing works
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 · see citing works
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 · see citing works
Wadgaonkar, R., & Collins, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.20.13760 · Cited by 93 · see citing works
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 · see citing works
Hay, T., & Meek, D. W. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01850-0 · Cited by 61 · see citing works
Flagged first, then by citations
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 · see citing works
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 1,556 · see citing works
“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 1,184 · see citing works
“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 1,063 · see citing works
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 · see citing works
Signal Transduction in CancerPreprint
Sever, R., & Brugge, J. S. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006098 · Cited by 992 · see citing works
“Last, Akt-induced ubiquitylation anddegradation of p53 suppresses p53-induced apoptosis (Ogawara et al. 2002).”
BackgroundHydrogen peroxide sensing, signaling and regulation of transcription factors
Marinho, H. S., Real, C., Cyrne, L., Soares, H., & Antunes, F. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.006 · Cited by 851 · see citing works
“On the other hand the phosphorylation of MDM2 through the PI3K/AKT pathway promotes MDM2 nuclear import, resulting in TP53 nuclear export [278][279][280].”
Backgroundp53 represses c-Myc through induction of the tumor suppressor miR-145
Sachdeva, M., Zhu, S., Wu, F., Wu, H., Walia, V., Kumar, S. R., Elble, R. C., Watabe, K., & Mo, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808042106 · Cited by 841 · see citing works
“degradation, inactivation (dephosphorylation) of Akt increases the stability of p53 (16).”
BackgroundStructure, regulation and function of PKB/AKT—a major therapeutic target
Hanada, M., Feng, J., & Hemmings, B. A. (2003) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2003.11.009 · Cited by 719 · see citing works
PI3K/Akt: getting it right matters
Franke, T. F. (2008) · Oncogene · doi:10.1038/onc.2008.313 · Cited by 696 · see citing works
“Two proposed mechanisms of Aktdependent regulation of Mdm2 include the Akt-dependent increase of Mdm2’s nuclear import (Mayo and Donner, 2001) and its intrinsic ubiquitin ligase activity (Zhou et al., 2001; Ashcroft et al., 2002; Ogawara et al., 2002).”
BackgroundThe PI3K/AKT/mTOR interactive pathway
Ersahin, T., Tuncbag, N., & Cetin-Atalay, R. (2015) · Molecular BioSystems · doi:10.1039/c5mb00101c · Cited by 683 · see citing works
Cheng, T., Liu, D., Griffin, J. H., Fernández, J. A., Castellino, F., Rosen, E. D., Fukudome, K., & Zloković, B. V. (2003) · Nature Medicine · doi:10.1038/nm826 · Cited by 560 · 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
“The 491 residues of HDM2 can be divided into three functional domains: an N-terminal region which binds p53, a Cterminal RING finger domain that promotes p53 ubiquitination, and a central region of approximately 300 residues that contains multiple sites for binding and regulation by different proteins, including RB (1…”
BackgroundBrazil, D. P., Park, J., & Hemmings, B. A. (2002) · Cell · doi:10.1016/s0092-8674(02)01083-8 · Cited by 537 · see citing works
Freeman, D. J., Li, A. G., Wei, G., Li, H.-H., Kertesz, N. L., Lesche, R., Whale, A. D., Martinez-Diaz, H., Rozengurt, N., Cardiff, R. D., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00021-7 · Cited by 512 · see citing works
“These results indicate that the endogenous p53 transcriptional activity Our study, together with those of others (Mayo et al., 2002; Mayo and Donner, 2001; Ogawara et al., 2002; Zhou et al., is indeed controlled by the PTEN tumor suppressor. 2001), may also help to explain why concomitant mutations in both p53 and PTE…”
BackgroundResultA negative feedback signaling network underlies oncogene-induced senescence
Courtois-Cox, S., Genther Williams, S. M., Reczek, E. E., Johnson, B. W., McGillicuddy, L. T., Johannessen, C. M., Hollstein, P. E., MacCollin, M., & Cichowski, K. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.003 · Cited by 501 · see citing works
“Notably, MDM2 phosphorylation by AKT at serine 166 (and 186) has been reported to activate its ubiquitin ligase activity toward p53 (Ogawara et al., 2002).”
BackgroundUbiquitin ligases in oncogenic transformation and cancer therapy
Senft, D., Qi, J., & Ronai, Z. A. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.105 · Cited by 490 · see citing works
GSK3 and its interactions with the PI3K/AKT/mTOR signalling network
Hermida, M. A., Kumar, J. D., & Leslie, N. R. (2017) · Advances in Biological Regulation · doi:10.1016/j.jbior.2017.06.003 · Cited by 482 · see citing works
“…1 (Carpenter et al., 2015; Dayalan Naidu and Dinkova-Kostova, 2017) HIF1 a (Masoud and Li, 2015; Mottet et al., 2003) MDM2 (Kulikov et al., 2005; Ogawara et al., 2002; Zhou et al., 2001) MLK3 (Figueroa et al., 2003) NDRG1 (Murray et al., 2004; Sommer et al., 2013; Zurashvili et al., 2013) TSC2…”
The critical role of Akt in cardiovascular function
Abeyrathna, P., & Su, Y. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.05.008 · Cited by 428 · see citing works
The MDM2-p53 pathway revisited
Nag, S. A., Jiangjiang, Q., Kalkunte, S. S., Ming-hai, W., & Zhang, R. (2013) · Journal of Biomedical Research · doi:10.7555/jbr.27.20130030 · Cited by 414 · see citing works
“Another facet of MDM2 regulation involves posttranslational modifications([43]) including phosphorylation of the MDM2 protein by upstream molecules such as ATM (decreases MDM2 stability)([43-45]) and Akt (increases MDM2 translocation from the cytoplasm into the nucleus, allowing p53 degradation)([46-49]).”
BackgroundIwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390 · see citing works
Physiological regulation of Akt activity and stability.
Liao, Y., & Hung, M. (2010) · PubMed Central · Cited by 343 · see citing works
The p53 response to DNA damage
Meek, D. W. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.027 · Cited by 329 · see citing works
PI3k/AKT signaling pathway: Erythropoiesis and beyond
Jafari, M., Ghadami, E., Dadkhah, T., & Akhavan‐Niaki, H. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27262 · Cited by 322 · see citing works
“Also, it prevents the expression of P21 through phosphorylation and activation of MDM2 and regulates therefore negatively P53 (Li, Dowbenko, & Lasky, 2002; Ogawara et al., 2002; Z. Yuan et al., 2005; B. P. Zhou et al., 2001).”
BackgroundActivation of PI3K‐Akt signaling pathway promotes prostate cancer cell invasion
Shukla, S., MacLennan, G. T., Hartman, D. J., Fu, P., Resnick, M. I., & Gupta, S. (2007) · International Journal of Cancer · doi:10.1002/ijc.22862 · Cited by 316 · see citing works
“Akt has been shown to prolong cell survival by delaying p53-dependent apoptosis through MDM2 phosphorylation.(19) Akt has also been shown to inhibit the Raf-MEK-ERK pathway through phosphorylation of Raf-1 and to overcome constitutively activated MAPK-induced cell cycle arrest.”
BackgroundAkt: A Double-Edged Sword in Cell Proliferation and Genome Stability
Xu, N., Lao, Y., Zhang, Y., & Gillespie, D. A. (2012) · Journal of Oncology · doi:10.1155/2012/951724 · Cited by 304 · see citing works
“In response to growth factor stimulation, active Akt binds to and phosphorylates Mdm2 at Ser166 and Ser186 to enhance protein stability and facilitate the function of Mdm2 to promote p53 ubiquitination [73, 74].”
BackgroundAstle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D., & Pearson, R. B. (2012) · Oncogene · doi:10.1038/onc.2011.394 · Cited by 295 · see citing works
“These results are intriguing given that previous reports demonstrate that AKT promotes the activity of the E3 ubiquitin ligase MDM2 (Ogawara et al., 2002), the important negative regulator of p53 (Haupt et al.”
BackgroundResultInfluentialFeng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404936200 · Cited by 294 · see citing works
Targeting AKT for cancer therapy
Shariati, M., & Meric‐Bernstam, F. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1676726 · Cited by 295 · see citing works
Negative and positive regulation of HIF-1: A complex network
Bárdos, J. I., & Ashcroft, M. A. (2005) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2005.05.001 · Cited by 282 · see citing works
Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma
Sun, E. J., Wankell, M., Palamuthusingam, P., McFarlane, C., & Hebbard, L. (2021) · Biomedicines · doi:10.3390/biomedicines9111639 · Cited by 287 · see citing works
Posttranslational modification of MDM2.
Meek, D. W., & Knippschild, U. (2003) · PubMed · Cited by 280 · see citing works
Regulation of the human catalytic subunit of telomerase (hTERT)
Daniel, M. G., Peek, G. W., & Tollefsbol, T. O. (2012) · Gene · doi:10.1016/j.gene.2012.01.095 · Cited by 265 · see citing works
“…the NF-κB pathway, disrupt cell cycle control and advance cell cycle progression by either the degradation or down-regulation of p53, p21, and p27 (Ogawara et al., 2002; Bai et al., 2009; Li and Sarkar, 2002; Tomoda et al., 2002; Oh et al., 2006; Hsu et al., 2007; Johnson et al., 2010; Wan et…”
BackgroundAn Shp2/SFK/Ras/Erk Signaling Pathway Controls Trophoblast Stem Cell Survival
Yang, W., Klaman, L. D., Chen, B., Araki, T., Harada, H., Thomas, S. Μ., George, E. L., & Neel, B. G. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.01.002 · Cited by 266 · see citing works
Sensitivity of Salivary Glands to Radiation: from Animal Models to Therapies
Grundmann, O., Mitchell, G. C., & Limesand, K. H. (2009) · Journal of Dental Research · doi:10.1177/0022034509343143 · Cited by 262 · see citing works
“3), which binds to p53 and targets it for degradation by the proteasome (Ogawara et al., 2002).”
BackgroundThe complexity of p53-mediated metabolic regulation in tumor suppression
Liu, Y., & Gu, W. J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.010 · Cited by 260 · see citing works
Mochizuki, T., Furuta, S., Mitsushita, J., Shang, W. H., Ito, M., Yokoo, Y., Yamaura, M., Ishizone, S., Nakayama, J., Konagai, A., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209406 · Cited by 253 · see citing works
“0 wt AKT1 and AKT1 Lys179Ala were previously described (Ogawara et al., 2002).”
BackgroundHallstrom, T. C., Mori, S., & Nevins, J. R. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.11.031 · Cited by 249 · see citing works
“activation of NFκB transcription of pro-survival targets by inducing degradation of IκB, an inhibitor of NFκB function (Ashcroft et al., 2002; Ogawara et al., 2002).”
BackgroundLo, H., Hsu, S.-C., & Hung, M. (2005) · Breast Cancer Research and Treatment · doi:10.1007/s10549-005-9011-0 · Cited by 237 · see citing works
“Specifically, Akt phosphorylates MDM2 at Ser166/186 and enhances its association with p300, but inhibits its interaction with p19, leading to robust degradation of p53 [42,56].”
BackgroundA systematic review of p53 regulation of oxidative stress in skeletal muscle
Beyfuss, K. A., & Hood, D. A. (2018) · Redox Report · doi:10.1080/13510002.2017.1416773 · Cited by 239 · see citing works
“Atorvastatin, on the other hand, is a medicinal statin used to treat diabetes and high cholesterol, and serves to reduce p53 accumulation by increasing IRS-1/ Akt phosphorylation of Mdm2 to upregulate p53 ubiquitination and degradation [67,115].”
BackgroundAKT and ERK dual inhibitors: The way forward?
Cao, Z., Liao, Q., Su, M., Huang, K., Jin, J., & Cao, D. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.025 · Cited by 234 · see citing works
Tsugawa, H., Suzuki, H., Saya, H., Hatakeyama, M., Hirayama, T., Hirata, K., Nagano, O., Matsuzaki, J., & Hibi∥, T. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.10.014 · Cited by 231 · see citing works
“Activation of the Akt Pathway Depends on the Accumulation of ROS for Autophagy Induction Phosphorylated Akt enhances the ubiquitination-promoting function of MDM2 by phosphorylation, resulting in p53 downregulation (Ogawara et al., 2002).”
BackgroundMyocardial AKT: The Omnipresent Nexus
Sussman, M. A., Völkers, M., Fischer, K. M., Bailey, B., Cottage, C. T., Din, S., Gude, N. A., Avitabile, D., Alvarez, R., Sundararaman, B., et al. (2011) · Physiological Reviews · doi:10.1152/physrev.00024.2010 · Cited by 229 · see citing works
Ishikawa, M., Iwamoto, T., Nakamura, T., Doyle, A. D., Fukumoto, S., & Yamada, Y. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201101050 · Cited by 227 · see citing works
“Akt-mediated MDM2 phosphorylation leads to p53 ubiquitination (Ogawara et al., 2002).”
PI3K/Akt-mediated regulation of p53 in cancer
Abraham, A., & O’Neill, E. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140070 · Cited by 220 · see citing works
p53 Activation in Adipocytes of Obese Mice
Yahagi, N., Shimano, H., Matsuzaka, T., Najima, Y., Sekiya, M., Nakagawa, Y., Ide, T., Tomita, S., Okazaki, H., Tamura, Y., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302364200 · Cited by 220 · see citing works
The importance of p53 location: nuclear or cytoplasmic zip code?
O’Brate, A., & Giannakakou, P. (2003) · Drug Resistance Updates · doi:10.1016/j.drup.2003.10.004 · Cited by 207 · see citing works
“Mayo et al. (2002), Mayo and Donner (2001), Ogawara et al. (2002), Sabbatini and McCormick (1999), Stambolic et al. (2001), Zhou et al. (2001) c-Abl–MDM2 c-Abl binds to MDM2 and prevents its interaction with p53 resulting in nuclear retention of p53 Goldberg et al. (2002) Cytoplasmic anchorage and…”
BackgroundAKT/PKB signaling mechanisms in cancer and chemoresistance
Donghwa, K. (2005) · Frontiers in bioscience · doi:10.2741/1592 · Cited by 204 · see citing works
“Akt targets several key cell cycle regulators including p21cip1/waf1, p27kip1, and MDM2.”
InfluentialEmerging role of PI3K/AKT in tumor-related epigenetic regulation
Yang, Q., Jiang, W., & Hou, P. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.04.001 · Cited by 206 · see citing works
Skinner, H. D., Zheng, J. Z., Fang, J. S., Agani, F. H., & Jiang, B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404097200 · Cited by 194 · see citing works
Fraser, M. E., Leung, B. M., Yan, X., Dan, H. C., Cheng, J. Q., & Tsang, B. K. (2003) · PubMed · Cited by 187 · see citing works
Chibaya, L., Karim, B. O., Zhang, H., & Jones, S. N. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003193118 · Cited by 191 · see citing works
“These cell-based studies suggest that AKT-MDM2 signaling may participate in the DNA damage response of cells to IR.”
BackgroundInfluentialFraser, M. E., Bai, T., & Tsang, B. K. (2007) · International Journal of Cancer · doi:10.1002/ijc.23086 · Cited by 175 · see citing works
p53 and NF‐κB: different strategies for responding to stress lead to a functional antagonism
Ak, P., & Levine, A. J. (2010) · The FASEB Journal · doi:10.1096/fj.10-160549 · Cited by 178 · see citing works
Chemoresistance in human ovarian cancer: the role of apoptotic regulators
Fraser, M. E., Leung, B. M., Jahani‐Asl, A., Yan, X., Thompson, W. E., & Tsang, B. K. (2003) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-1-66 · Cited by 170 · see citing works
Yin, X., Pavone, M. E., Lu, Z., Wei, J., & Kim, J. J. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1527 · Cited by 171 · see citing works
“Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N, Gotoh Y 2002 Akt enhances Mdm2-mediated ubiquitination and degradation of p53.”
BackgroundMechanistic Insights into Maintenance of High p53 Acetylation by PTEN
Li, A. G., Piluso, L. G., Cai, X., Wei, G., Sellers, W. R., & Liu, X. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.06.028 · Cited by 167 · see citing works
“L344A dimers retain specific DNA binding activity ( McLure and Lee, 1998 ) but fail to interact with PTEN (Figures 5D and 5E).”
BackgroundThe role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
Gao, M., & Karin, M. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.08.017 · Cited by 159 · see citing works
Specificity in the activation and control of transcription factor E2F-dependent apoptosis
Hallstrom, T. C., & Nevins, J. R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1831408100 · Cited by 152 · see citing works
CD49f Enhances Multipotency and Maintains Stemness Through the Direct Regulation of OCT4 and SOX2
Yu, K., Yang, S., Jung, J., Kim, S., Ko, K., Han, D., Park, S., Choi, S. W., Kang, S., Schöler, H. R., et al. (2012) · Stem Cells · doi:10.1002/stem.1052 · Cited by 150 · see citing works
An Emerging Class of Long Non-coding RNA With Oncogenic Role Arises From the snoRNA Host Genes
Zimța, A., Țigu, A. B., Braicu, C., Stefan, D. C., Ionescu, C., & Berindan‐Neagoe, I. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00389 · Cited by 150 · see citing works
“This signaling pathway is a master regulator of cell activity, and it acts by inhibiting p21, p53, and BAX, while activating the MDM2 oncogene (141, 142).”
BackgroundRegulation of Cellular Metabolism and Hypoxia by p53Preprint
Humpton, T. J., & Vousden, K. H. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026146 · Cited by 147 · see citing works
“Decreased AKT signaling (in response to nutrient starvation) leads to the suppression of MDM2 activity and, thus, promotes stabilization of p53 (Mayo and Donner 2001; Ogawara et al. 2002; Feng et al. 2004).”
BackgroundProtein kinase B: signalling roles and therapeutic targeting
Sale, E. M., & Sale, G. J. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7274-9 · Cited by 142 · see citing works
PI-3-K and AKT: Onto the mitochondria☆
Stiles, B. L. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2009.07.017 · Cited by 144 · see citing works
“Mdm2 negatively regulates p53 by acting as an E3 ubiquitin ligase for p53 and an inhibitor of p53 transcriptional activation [63].”
BackgroundProtein post-translational modifications in the regulation of cancer hallmarks
Wang, H., Yang, L., Liu, M., & Luo, J. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-022-00464-3 · Cited by 144 · see citing works
Phosphorylation of AKT: a Mutational Analysis
Hart, J. R., & Vogt, P. K. (2011) · Oncotarget · doi:10.18632/oncotarget.293 · Cited by 141 · see citing works
“Major targets of AKT include the TSC1-TSC2 (tuberous sclerosis) complex which mediates TORC1 (target of rapamycin complex 1) activation [6], the forkhead transcription factors FOXO1 (Forkhead box) and FOXO3a which regulate cell death, morphology and function as tumor suppressors [9-13], MDM2 (murine double minute) whi…”
BackgroundThe central region of HDM2 provides a second binding site for p53
Yu, G. W., Rüdiger, S., Veprintsev, D. B., Freund, S. M. V., Fernández-Fernández, M. R., & Fersht, A. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510343103 · Cited by 139 · see citing works
Gagarina, V., Gabay, O., Dvir‐Ginzberg, M., Lee, E. J., Brady, J. K., Quon, M. J., & Hall, D. J. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27369 · Cited by 137 · see citing works
Wu, W. D., Chen, Z.-J., Zhang, K.-S., Yang, X.-L., Wu, Y.-M., Chen, X.-H., Huang, H.-B., Liu, H.-L., Cai, S.-H., Du, J., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.398 · Cited by 136 · see citing works
“In normal, p53 levels are low due to continuous MDM2-mediated ubiquitination and degradation.(42) Our results indicated that G-1 treatment significantly downregulated the mRNA of MDM2 and upregulated the mRNA and protein of p53 via a time-dependent manner.”
BackgroundRAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy
Yajima, I., Kumasaka, M. Y., Thang, N. D., Goto, Y., Takeda, K., Yamanoshita, O., Iida, M., Ohgami, N., Tamura, H., Kawamoto, Y., et al. (2011) · Dermatology Research and Practice · doi:10.1155/2012/354191 · Cited by 136 · see citing works
“MDM2 is also a substrate for AKT [54–56].”
BackgroundAmin, A. R. M. R., Karpowicz, P. A., Carey, T. E., Arbiser, J. L., Nahta, R., Chen, Z. G., Dong, J., Küçük, Ö., Khan, G. N., Huang, G. S., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.02.005 · Cited by 136 · see citing works
“signaling, enhances MDM2-mediated ubiquitination and proteosomal degradation of p53 [195].”
BackgroundHedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2
Abe, Y., Oda-Sato, E., Tobiume, K., Kawauchi, K., Taya, Y., Okamoto, K., Oren, M., & Tanaka, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712216105 · Cited by 135 · see citing works
“S166 and S186 are known to be phosphorylated by Akt, which activates the Mdm2-mediated degradation of p53 (22, 23).”
BackgroundSzymonowicz, K., Oeck, S., Malewicz, N. M., & Jendrossek, V. (2018) · Cancers · doi:10.3390/cancers10030078 · Cited by 134 · see citing works
Induction of Akt Activity by Chemotherapy Confers Acquired Resistance
Huang, W., & Hung, M. (2009) · Journal of the Formosan Medical Association · doi:10.1016/s0929-6646(09)60051-6 · Cited by 133 · see citing works
Bogoyevitch, M. A. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.03.017 · Cited by 132 · see citing works
“For example, Akt can phosphorylate Mdm2 to enhance its ubiquitin ligase activity and hence degradation of p53 [50].”
BackgroundMelanoma: From Melanocyte to Genetic Alterations and Clinical Options
Bertolotto, C. (2013) · Scientifica · doi:10.1155/2013/635203 · Cited by 131 · see citing works
“AKT enhances Mdm2-mediated ubiquitination and degradation of p53 [200] and p53 regulates the epithelial-mesenchymal transition [201].”
BackgroundCytokinesis, ploidy and aneuploidy
Lacroix, B., & Maddox, A. (2012) · Journal of Pathology · doi:10.1002/path.3013 · Cited by 144 · see citing works
Dysregulation of cellular signaling by HER2 in breast cancer
Zhou, B. P. (2003) · Seminars in Oncology · doi:10.1053/j.seminoncol.2003.08.006 · Cited by 127 · see citing works
MDM2 and MDMX: Alone and together in regulation of p53.
Shadfan, M., Lopez-Pajares, V., & Yuan, Z.-M. (2012) · PubMed · Cited by 125 · see citing works
Silber, J., Skanderup, A. J., Ozawa, T., Harinath, G., Pedraza, A. M., Sander, C., Holland, E. C., & Huse, J. T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033844 · Cited by 125 · see citing works
“Indeed, earlier work has identified a potential conduit for such transcriptional regulation through p-AKT and p-MDM2 [15].”
BackgroundInfluentialGuo, S., Ye, H., Teng, Y., Wang, Y.-L., Yang, G., Li, X.-B., Zhang, C., Yang, X., Yang, Z., & Yang, X. Y. (2013) · Nature Communications · doi:10.1038/ncomms3544 · Cited by 123 · see citing works
Uko, N. E., Güner, O. F., Matesic, D. F., & Bowen, J. P. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200224101808 · Cited by 123 · see citing works
Alam, H., Weck, J., Maizels, E. T., Park, Y., Lee, E. J., Ashcroft, M. A., & Hunzicker-Dunn, M. E. (2008) · Endocrinology · doi:10.1210/en.2008-0850 · Cited by 121 · see citing works
Castillo, S. S., Brognard, J., Petukhov, P. A., Zhang, C., Tsurutani, J., Granville, C. A., Li, M., Jung, M., West, K. A., Gills, J. G., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1530 · Cited by 121 · see citing works
Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms
Maugeri, A., Calderaro, A., Patanè, G. T., Navarra, M., Barreca, D., Cirmi, S., & Felice, M. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032952 · Cited by 120 · see citing works
p53 and the Carcinogenicity of Chronic InflammationPreprint
Gudkov, A. V., & Komarova, E. A. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026161 · Cited by 122 · see citing works
“The inhibitory effect of PI3K/AKT-1 signaling on p53 activity can involve AKT-1mediated phosphorylation and inactivation of p53-regulated proapoptotic factors (Datta et al. 1997) as well as AKT-1-mediated phosphorylation of Mdm2 (Ogawara et al. 2002), which increases p53 degradation.”
BackgroundInfluentialSignaling, metabolism, and cancer: An important relationship for therapeutic intervention
Vaghari‐Tabari, M., Ferns, G. A., Qujeq, D., Andevari, A. N., Sabahi, Z., & Moein, S. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30276 · Cited by 117 · see citing works
“on some proapoptotic proteins such as Bad and the well‐known tumor suppressor p53 causes resistance to apoptosis (Datta et al., 1997; Gottlieb et al., 2002; Ogawara et al., 2002).”
BackgroundMehta, R. R., Yamada, T., Taylor, B. N., Christov, K. T., King, M. L., Majumdar, D., Lekmine, F., Tiruppathì, C., Shilkaitis, A. L., Bratescu, L., et al. (2011) · Angiogenesis · doi:10.1007/s10456-011-9220-6 · Cited by 115 · see citing works
“Akt-mediated phosphorylation of MDM2 decreases its association with p53, reducing the rate of its degradation [50, 55].”
BackgroundInfluentialTumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection
Siegl, C., Prusty, B. K., Rajeeve, K., Wischhusen, J., & Rudel, T. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.004 · Cited by 109 · see citing works
“Akt directly activates HDM2 by phosphorylation of Ser166 and Ser186 (Ogawara et al., 2002), and in agreement with this, we found increased phosphorylated HDM2 in infected cells (Figures 3A and 3B).”
BackgroundAllavena, G., Carrarelli, P., Bello, B. D., Luisi, S. V., Petraglia, F., & Maellaro, E. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2015.02.007 · Cited by 109 · see citing works
“To explain the p53 down-regulation, two major autophagy-independent mechanisms can be evoked, both related to Akt pathway, the latter proved to be overactivated in endometriotic tissues and cells from ovarian endometriomas (25, 26): the first mechanism is the transcriptional down-regulation of p53, through Akt-mediate…”
BackgroundPlumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo
Sinha, S., Pal, K., Elkhanany, A. M., Dutta, S. K., Cao, Y., Mondal, G., Iyer, S. R., Somasundaram, V., Couch, F. J., Shridhar, V., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.27724 · Cited by 108 · see citing works
Myocardial Aging and Senescence: Where Have the Stem Cells Gone?
Sussman, M. A., & Anversa, P. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.66.032102.140723 · Cited by 108 · see citing works
Regulation of the p53-MDM2 pathway by 14-3-3 σ and other proteins
Lee, M., & Lozano, G. (2006) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2006.03.009 · Cited by 108 · see citing works
Regulation of p53 - insights into a complex process
Boehme, K. A., & Blattner, C. (2009) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409230903401507 · Cited by 106 · see citing works
“Due to the increase in Mdm2 abundance, p53 degradation is enhanced upon Akt/PKB activation (Mayo and Donner, 2001; Zhou et al., 2001; Ashcroft et al., 2002; Ogawara et al., 2002; Feng et al., 2004; Danes et al., 2008).”
BackgroundTargeting prostate cancer based on signal transduction and cell cycle pathways
Lee, J. T., Lehmann, B. D., Terrian, D. M., Chappell, W. H., Stivala, F., Libra, M., Martelli, A. M., Steelman, L. S., & McCubrey, J. A. (2008) · Cell Cycle · doi:10.4161/cc.7.12.6166 · Cited by 104 · see citing works
The Trk A, B, C's of Neurotrophins in the Cochlea
Green, S. H., Bailey, E. M., Wang, Q., & Davis, R. L. (2012) · The Anatomical Record · doi:10.1002/ar.22587 · Cited by 104 · see citing works
“For example, Akt phosphorylates and inactivates proapoptotic transcription factors of the Forkhead/FoxO family (Brunet et al., 1999) and p53 (Ogawara et al., 2002) and Akt phosphorylates and inactivates the proapoptotic Bcl-2 family protein Bad (Downward, 1999).”
BackgroundSumoylation of Mdm2 by Protein Inhibitor of Activated STAT (PIAS) and RanBP2 Enzymes
Miyauchi, Y., Yogosawa, S., Honda, R., Nishida, T., & Yasuda, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208319200 · Cited by 102 · see citing works
Molecular determinants of Akt-induced keratinocyte transformation
Segrelles, C., Moral, M., Lara, M. F., Ruiz, S., Santos, M., Leis, H., García‐Escudero, R., Martínez‐Cruz, A. B., Martínez‐Palacio, J., Hernández, P., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209155 · Cited by 102 · see citing works
“In addition, Akt can also phosphorylate mdm2, favoring mdm2–p53 association and leading to subsequent p53 degradation (Mayo and Donner, 2001; Ogawara et al., 2002; Zhou and Hung, 2002).”
BackgroundWei, S., Chen, X., McGraw, K. L., Zhang, L., Komrokji, R. S., Clark, J., Cáceres, G., Billingsley, D., Sokol, L., Lancet, J. E., et al. (2012) · Oncogene · doi:10.1038/onc.2012.139 · Cited by 102 · see citing works
- 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
