p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Open accessAbstract
The tumor suppressor p53 is activated upon genotoxic and oxidative stress and in turn inhibits cell proliferation and growth through induction of specific target genes. Cell growth is positively regulated by mTOR, whose activity is inhibited by the TSC1:TSC2 complex. Although genotoxic stress has been suggested to inhibit mTOR via p53-mediated activation of mTOR inhibitors, the precise mechanism of this link was unknown. We now demonstrate that the products of two p53 target genes, Sestrin1 and Sestrin2, activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR. Correspondingly, Sestrin2-deficient mice fail to inhibit mTOR signaling upon genotoxic challenge. Sestrin1 and Sestrin2 therefore provide an important link between genotoxic stress, p53 and the mTOR signaling pathway.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
p53 uses two direct target genes, SESN1 and SESN2, to block mTOR and to repress mRNA translation.
“In addition, p53 uses two direct target genes, SESN1 and SESN2, to block mTOR and to repress mRNA translation.211, 215”
From Census and evaluation of p53 target genes (2017) · cites this paper as [211]
P53 can further block mTOR activity through its direct target genes SESN1 and SESN2.
“P53 can further block mTOR activity through its direct target genes SESN1 and SESN2.211”
From Census and evaluation of p53 target genes (2017) · cites this paper as [211]
Sestrins regulate mTORC1 activity by binding AMPK, activating it and repressing mTORC1 activity.
“Sestrins are able to bind AMPK activating it and, by this mechanism, repress mTORC1 activity (Budanov and Karin, 2008).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Budanov and Karin, 2008
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · see citing works
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652 · see citing works
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181 · see citing works
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · see citing works
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833 · see citing works
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.054 · Cited by 2,665 · see citing works
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,659 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911 · see citing works
mTOR and cancer: insights into a complex relationship
Sabatini, D. M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1974 · Cited by 1,322 · see citing works
Postic, C., Shiota, M., Niswender, K. D., Jetton, T. L., Chen, Y., Moates, J. M., Shelton, K. D., Lindner, J., Cherrington, A. D., & Magnuson, M. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.1.305 · Cited by 1,302 · see citing works
Fingar, D. C., & Blenis, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207542 · Cited by 1,250 · see citing works
The coordinate regulation of the p53 and mTOR pathways in cells
Feng, Z., Zhang, H., Levine, A. J., & Jin, S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502857102 · Cited by 1,235 · see citing works
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C., & Blenis, J. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00506-2 · Cited by 1,211 · see citing works
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1432 · Cited by 1,139 · see citing works
The antioxidant function of the p53 tumor suppressor
Sablina, A. A., Budanov, A. V., Ilyinskaya, G. V., Agapova, L. S., Kravchenko, J. E., & Chumakov, P. M. (2005) · Nature Medicine · doi:10.1038/nm1320 · Cited by 1,110 · see citing works
Self-citationJonkers, J., Meuwissen, R. L. J., van der Gulden, H. M. L., Peterse, H. L., van der Valk, M., & Berns, A. J. M. (2001) · Nature Genetics · doi:10.1038/ng747 · Cited by 1,053 · see citing works
Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00220-x · Cited by 1,043 · see citing works
Regulation of cap-dependent translation by eIF4E inhibitory proteins
Richter, J. D., & Sonenberg, N. (2005) · Nature · doi:10.1038/nature03205 · Cited by 972 · see citing works
Fingar, D. C., Richardson, C. J., Tee, A. R., Cheatham, L. A., Tsou, C., & Blenis, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.200-216.2004 · Cited by 865 · see citing works
Pende, M., Um, S. H., Mieulet, V., Sticker, M., Goss, V. L., Mestan, J., Mueller, M., Fumagalli, S., Kozma, S. C., & Thomas, G. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.8.3112-3124.2004 · Cited by 743 · see citing works
Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD
Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V., & Chumakov, P. M. (2004) · Science · doi:10.1126/science.1095569 · Cited by 731 · see citing works
Self-citationRibosomal S6 Kinase Signaling and the Control of Translation
Dufner, A., & Thomas, G. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4683 · Cited by 676 · cited 3× · see citing works
“p70S6K activation can in turn be determined by phosphorylation of ribosomal S6 protein at S235/236 (Dufner and Thomas, 1999; Pende et al., 2004).”
Feng, Z., Hu, W., de Stanchina, E., Teresky, A. K., Jin, S., Lowe, S., & Levine, A. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4149 · Cited by 633 · see citing works
Yang, Q., & Guan, K. (2007) · Cell Research · doi:10.1038/cr.2007.64 · Cited by 540 · see citing works
AMPK and cell proliferation – AMPK as a therapeutic target for atherosclerosis and cancer
Motoshima, H., Goldstein, B. J., Igata, M., & Araki, E. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108324 · Cited by 529 · see citing works
An expanding role for mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2005.06.007 · Cited by 519 · see citing works
Verna, L. (1996) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(96)00062-9 · Cited by 514 · see citing works
eIF4E – from translation to transformation
Mamane, Y., Petroulakis, E., Rong, L., Yoshida, K., Ler, L. W., & Sonenberg, N. (2004) · Oncogene · doi:10.1038/sj.onc.1207549 · Cited by 452 · see citing works
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
Kwiatkowski, D. J., & Manning, B. D. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi260 · Cited by 395 · see citing works
Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?
Corradetti, M. N., & Guan, K.-L. (2006) · Oncogene · doi:10.1038/sj.onc.1209885 · Cited by 387 · see citing works
Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability
Budanov, A. V., Shoshani, T., Faerman, A., Zelin, E., Kamer, I., Kalinski, H., Gorodin, S., Fishman, A., Chajut, A., Einat, P., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205877 · Cited by 363 · see citing works
Self-citationCoordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways
Levine, A. J., Feng, Z., Mak, T. W., You, H., & Jin, S. (2006) · Genes & Development · doi:10.1101/gad.1363206 · Cited by 321 · see citing works
Velasco-Miguel, S., Buckbinder, L., Jean, P., Gelbert, L., Talbott, R. L., Laidlaw, J. L., Seizinger, B. R., & Kley, N. (1999) · Oncogene · doi:10.1038/sj.onc.1202274 · Cited by 249 · see citing works
Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex
Sarbassov, D. D., & Sabatini, D. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506096200 · Cited by 248 · see citing works
When translation meets transformation: the mTOR story
Avérous, J., & Proud, C. G. (2006) · Oncogene · doi:10.1038/sj.onc.1209887 · Cited by 197 · see citing works
Averous, J., Fonseca, B. D., & Proud, C. G. (2008) · Oncogene · doi:10.1038/sj.onc.1210715 · Cited by 194 · see citing works
MDM2 Gene Amplification and Transcript Levels in Human Sarcomas: Relationship to TP53 Gene Status
Flørenes, V. A., Mælandsmo, G. M., Forus, A., Andreassen, Å. K., Myklebost, O., & Fodstad, Ø. (1994) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/86.17.1297 · Cited by 188 · see citing works
Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival
Ragnarsson, G., Eiriksdottir, G., Johannsdottir, J. T., Jonasson, J. G., Egilsson, V., & Ingvarsson, S. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690234 · Cited by 159 · see citing works
Astrinidis, A., Cash, T. P., Hunter, D., Walker, C. L., Chernoff, J., & Henske, E. P. (2002) · Oncogene · doi:10.1038/sj.onc.1205962 · Cited by 151 · see citing works
Dames, S. A., Mulet, J. M., Rathgeb–Szabo, K., Hall, M. N., & Grzesiek, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501116200 · Cited by 130 · see citing works
Zonation of cytochrome P450 isozyme expression and induction in rat liver
Bühler, R., Lindros, K. O., Nordling, Å., Johansson, I., & Ingelman‐Sundberg, M. (1992) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1992.tb16650.x · Cited by 123 · see citing works
Peeters, H., Debeer, P., Bairoch, A., Wilquet, V., Huysmans, C., Parthoens, E., Fryns, J. P., Gewillig, M. H. M. L., Nakamura, Y., Niikawa, N., et al. (2003) · Human Genetics · doi:10.1007/s00439-003-0917-5 · Cited by 117 · see citing works
Horton, L. E., Bushell, M., Baus, D., Tilleray, V. J., Clemens, M. J., & Hensold, J. O. (2002) · Oncogene · doi:10.1038/sj.onc.1205662 · Cited by 92 · see citing works
Guan, L., Song, K. W., Pysz, M. A., Curry, K., Hizli, A. A., Danielpour, D., Black, A. R., & Black, J. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610513200 · Cited by 81 · see citing works
mTOR and cancer: reason for dancing at the crossroads?
THOMAS, G. V. (2005) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2005.12.003 · Cited by 72 · see citing works
The mammalian target of rapamycin signaling network and gene regulation
Soliman, G. A. (2005) · Current Opinion in Lipidology · doi:10.1097/01.mol.0000169352.35642.06 · Cited by 56 · see citing works
Role of telomeric sequences in murine radiation-induced myeloid leukaemia
Meijne, E. I. M., Silver, A. R., Bouffler, S. D., Morris, D. J., van Kampen, E. W., Spanjer, S., Huiskamp, R., & Cox, R. (1996) · Genes Chromosomes and Cancer · doi:10.1002/(sici)1098-2264(199608)16:4 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · see citing works
“DNA damage induces the expression of Tsc2 and phosphatase and tensin homolog deleted on chromosome 10 (Pten), causing downregulation of the entire PI3K-mTORC1 axis (Feng et al., 2005; Stambolic et al., 2001), and activates AMPK through a mechanism that depends on the induction of Sestrin1/2 (Budanov and Karin, 2008).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
“Sestrin 1 and sestrin 2 are two transcriptional targets of p53 that are implicated in the DNA damage response, and it was recently shown that sestrins potently activate AMPK, thus mediating the p53-dependent suppression of mTOR activity upon DNA damag”
BackgroundBlinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · see citing works
“to negatively regulate the kinase mTOR (mammalian target of rapamycin), a central node in the control of protein synthesis (Budanov and Karin, 2008; Feng et al., 2007a) (Figure 1).”
BackgroundKlionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
D’Hulst, G., Soro-Arnaiz, I., Masschelein, E., Veys, K., Fitzgerald, G., Smeuninx, B., Kim, S., Deldicque, L., Blaauw, B., Carmeliet, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13889-6 · Cited by 2,310 · see citing works
Self-consumption: the interplay of autophagy and apoptosis
Mariño, G., Niso-Santano, M., Baehrecke, E. H., & Kroemer, G. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3735 · Cited by 2,172 · see citing works
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943 · see citing works
“43 , and this led to the discovery of sestrin 1 ( SESN1 ) and sestrin 2 ( SESN2 ) — p53 target genes that inhibit mTOR signallin”
BackgroundRegulation of Mammalian Autophagy in Physiology and Pathophysiology
Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcı́a-Arencibia, M., Green-Thompson, Z. W., Jiménez-Sánchez, M., Korolchuk, V. I., Lichtenberg, M., Luo, S., et al. (2010) · Physiological Reviews · doi:10.1152/physrev.00030.2009 · Cited by 1,726 · see citing works
Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis
Ouyang, L., Shi, Z., Zhao, S., Wang, F., Zhou, T., Liu, B., & Bao, J. (2012) · Cell Proliferation · doi:10.1111/j.1365-2184.2012.00845.x · Cited by 1,458 · see citing works
Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.
Lee, J., Giordano, S., & Zhang, J. (2012) · Biochemical Journal · doi:10.1042/bj20111451 · Cited by 1,438 · see citing works
Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders
O’Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. (2012) · Science · doi:10.1126/science.1227764 · Cited by 1,240 · see citing works
Sestrin2 is a leucine sensor for the mTORC1 pathway
Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aab2674 · Cited by 1,306 · see citing works
The Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes
Levine, A. J., & Puzio-Kuter, A. M. (2010) · Science · doi:10.1126/science.1193494 · Cited by 1,243 · see citing works
Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress
Sengupta, S., Peterson, T. R., & Sabatini, D. M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.026 · Cited by 1,234 · see citing works
“…all act to inhibit mTORC1 as discussed earlier (Ellisen et al., 2002; Feng et al., 2005; Stambolic et al., 2001). p53 also transactivates Sestrin1 and Sestrin 2, which can repress mTORC1 via AMPK-dependent regulation of the TSC1/TSC2 complex (Budanov and Karin, 2008; Feng et al., 2005) (Figure 2).”
BackgroundAutophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182 · see citing works
Proteasomal and Autophagic Degradation Systems
Đikić, I. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044908 · Cited by 1,165 · see citing works
AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress
Jeon, S.-M., Chandel, N. S., & Hay, N. (2012) · Nature · doi:10.1038/nature11066 · Cited by 1,132 · see citing works
Regulation and function of AMPK in physiology and diseases
Jeon, S. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.81 · Cited by 1,122 · see citing works
Cytoplasmic functions of the tumour suppressor p53
Green, D. R., & Kroemer, G. (2009) · Nature · doi:10.1038/nature07986 · Cited by 1,106 · see citing works
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
P53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080 · see citing works
mTOR as a central hub of nutrient signalling and cell growth
Kim, J., & Guan, K. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0205-1 · Cited by 1,067 · see citing works
Regulation and function of mTOR signalling in T cell fate decisions
Chi, H. (2012) · Nature Reviews Immunology · doi:10.1038/nri3198 · Cited by 1,035 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks
Magnuson, B., Ekim, B., & Fingar, D. C. (2012) · Biochemical Journal · doi:10.1042/bj20110892 · Cited by 1,015 · see citing works
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
“The p53 target genes Sestrin1 and Sestrin2 phosphorylate and activate AMPK and promote autophagy.(178) p53 induces mitophagy by increasing the level of BNIP3.”
BackgroundVousden, K. H., & Ryan, K. M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2715 · Cited by 959 · see citing works
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
“Other new targets of p53-induced transcription have been identified that are involved in protein translatio”
BackgroundAMP-Activated Protein Kinase (AMPK) Controls the Aging Process via an Integrated Signaling Network
Salminen, A., & Kaarniranta, K. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2011.12.005 · Cited by 860 · see citing works
AMPK activators: mechanisms of action and physiological activities
Kim, J., Yang, G., Kim, Y., Kim, J., & Ha, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.16 · Cited by 817 · see citing works
Translational control in cancer
Silvera, D., Formenti, S. C., & Schneider, R. J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2824 · Cited by 820 · see citing works
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
Regulation of mTORC1 by amino acids
Bar-Peled, L., & Sabatini, D. M. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.003 · Cited by 773 · see citing works
“The TSC complex, whose loss underlies a hamartomatous syndrome of the same name (17, 18), serves as a central hub for numerous extracellular and intracellular inputs including mitogen and growth factor signaling (19-23), energy levels (24), oxygen availability (25, 26) and genotoxic stress (27), which collectively exe…”
Kubli, D. A., & Gustafsson, Å. B. (2012) · Circulation Research · doi:10.1161/circresaha.112.265819 · Cited by 792 · see citing works
“Many products of these target genes, such as AMP-activated protein kinase, tuberous sclerosis protein 2, and sestrin1/2 converge on the mTOR pathway.(80,81) mTOR is a negative regulator of autophagy, and inhibition of this pathway results in the induction of autophagy.”
BackgroundMolecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Nutrient sensing and TOR signaling in yeast and mammals
González, A., & Hall, M. (2017) · EMBO Journal · doi:10.15252/embj.201696010 · Cited by 684 · see citing works
“…proposed to repress mTORC1 through at least three different mechanisms: (i) by activating AMPK (AMP-activated protein kinase) and the TSC complex (Budanov & Karin, 2008), (ii) by acting as a GDI (guanosine dissociation inhibitor) to prevent GDP dissociation from RAGA/B (Peng et al , 2014), and…”
ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS
Alexander, A., Cai, S.-L., Kim, J., Nanez, A., Sahin, M., MacLean, K. H., Inoki, K., Guan, K.-L., Shen, J., Person, M. D., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913860107 · Cited by 717 · see citing works
“The p53-regulated genes Sestrin 1 and Sestrin 2 were shown to activate AMPK and repress mTORC1 signaling in response to camptothecin-induced genotoxic stress in a redoxindependent manner (21).”
BackgroundTranslational Regulation of Gene Expression during Conditions of Cell Stress
Spriggs, K. A., Bushell, M., & Willis, A. E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.028 · Cited by 721 · see citing works
“Signaling to mTOR, and thus 4EBP1, upon DNA damage appears to occur through a p53-dependent pathway requiring transcriptional activation of Sestrin1 and Sestrin2, which in turn activate AMP-responsive protein kinase (AMPK), which then activates the repressor of mTOR TSC2 (Budanov and Karin, 2008).”
BackgroundThe Lysosome as a Regulatory Hub
Perera, R. M., & Zoncu, R. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-125125 · Cited by 664 · see citing works
“Evidence for one of these pathways has recently emerged with the identification of the Sestrin1–3 proteins as upstream regulators of mTORC1 (Budanov & Karin 2008, Chantranupong et al. 2014, Parmigiani et al. 2014, Wolfson et al. 2016).”
BackgroundWith TOR, Less Is More: A Key Role for the Conserved Nutrient-Sensing TOR Pathway in Aging
Kapahi, P., Chen, D., Rogers, A. N., Katewa, S. D., Li, P. W.-L., Thomas, E., & Kockel, L. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.05.001 · Cited by 663 · see citing works
“Sestrin1 and Sestrin2, both transcriptional targets of the DNA damage sensor p53, activate AMPK, thereby inhibiting TOR pathway activity (Budanov and Karin, 2008).”
LKB1 and AMP-activated protein kinase control of mTOR signalling and growth
Shaw, R. J. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01972.x · Cited by 644 · see citing works
“Recently, the critical transcriptional targets of p53 that mediate the suppression of mTORC1 were identified as Sestrin1 and Sestrin2 (Budanov & Karin 2008).”
BackgroundBonora, M., Patergnani, S., Rimessi, A., De Marchi, E., Suski, J. M., Bononi, A., Giorgi, C., Marchi, S., Missiroli, S., Poletti, F., et al. (2012) · Purinergic Signalling · doi:10.1007/s11302-012-9305-8 · Cited by 644 · see citing works
“Several reports [34–36] have shown how p53 inhibits mTOR to repress cell growth and proliferation beyond genotoxic stress.”
BackgroundThe PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling
Shorning, B. Y., Dass, M. S., Smalley, M. J., & Pearson, H. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124507 · Cited by 638 · see citing works
“SESN1 and SESN2 are p53 target genes that are induced upon DNA damage and oxidative stress [217].”
BackgroundInterplay Between NLRP3 Inflammasome and Autophagy
Biasizzo, M., & Kopitar‐Jerala, N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.591803 · Cited by 620 · see citing works
“SESN2 was shown to induce autophagy through activation of AMPK and inhibition of mTOR (155, 156).”
BackgroundCellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway
Mo, J.-S., Meng, Z., Kim, Y. C., Park, H. W., Hansen, C. G., Kim, S., Lim, D.-S., & Guan, K.-L. (2015) · Nature Cell Biology · doi:10.1038/ncb3111 · Cited by 557 · see citing works
“Energy stress increases the interaction between AMPK and its physiological substrates 43–45 ; accordingly, AMPK co-precipitated with YAP and this interaction was further enhanced by 2-DG treatment (Fig.”
Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies
Lee, J. H., Budanov, A. V., Park, E. J., Birse, R., Kim, T. E., Perkins, G. A., Ocorr, K., Ellisman, M. H., Bodmer, R., Bier, E., et al. (2010) · Science · doi:10.1126/science.1182228 · Cited by 570 · see citing works
Self-citationmTOR complex 2 signaling and functions
Oh, W. J., & Jacinto, E. (2011) · Cell Cycle · doi:10.4161/cc.10.14.16586 · Cited by 561 · see citing works
The dawn of the age of amino acid sensors for the mTORC1 pathway
Wolfson, R. L., & Sabatini, D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.001 · Cited by 500 · see citing works
“Early reports argue that the Sestrins inhibit the mTORC1 pathway upstream of TSC and AMPK (Budanov and Karin, 2008), members of the growth factor sensing branch upstream of mTOR, but recent results are not compatible with this mechanism (Chantranupong et al., 2014; Peng et al., 2014).”
Nogueira, V., & Hay, N. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1424 · Cited by 516 · see citing works
Maiuri, M. C., Galluzzi, L., Morselli, E., Kepp, O., Malik, S. A., & Kroemer, G. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.12.001 · Cited by 498 · see citing works
“Genotoxic stress-induced p53-depedent upregulation has been observed also for the AMPK activators sestrins 1 and 2 [16], the latter of which has been shown to contribute — in p53-proficient cells — to the induction of autophagy by multiple triggers [16,17].”
BackgroundBae, S. H., Sung, S. H., Oh, S. Y., Lim, J. M., Lee, S. K., Park, Y. N., Lee, H. E., Kang, D., & Rhee, S. G. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.002 · Cited by 492 · see citing works
“Genotoxic stress inhibits mTORC1 signaling through activation of p53; Sesn2 is essential for this effect of p53 (Budanov and Karin, 2008).”
BackgroundComplex interplay between autophagy and oxidative stress in the development of pulmonary disease
Ornatowski, W., Lü, Q., Yegambaram, M., Flores, A. G., Zemskov, E. A., Maltepe, E., Fineman, J. R., Wang, T., & Black, S. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101679 · Cited by 474 · see citing works
Chantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466 · see citing works
“In addition, consistent with previous reports (Budanov and Karin, 2008), stable overexpression of FLAG-Sestrin2 caused a dramatic reduction in cell size (Figure 2B), a well-known consequence of mTORC1 inhibition (Fingar et al.”
InfluentialThe p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458 · see citing works
mTOR in aging, metabolism, and cancer
Cornu, M., Albert, V., & Hall, M. N. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.12.005 · Cited by 446 · see citing works
Metabolic Regulation by p53 Family Members
Berkers, C. R., Maddocks, O. D. K., Cheung, E. C., Mor, I., & Vousden, K. H. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.019 · Cited by 443 · see citing works
Metabolism of Amino Acids in Cancer
Wei, Z. C., Liu, X., Cheng, C., Yu, W., & Yi, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.603837 · Cited by 439 · see citing works
mTOR and cancer: many loops in one pathway
Efeyan, A., & Sabatini, D. M. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.10.007 · Cited by 427 · see citing works
“The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.”
BackgroundInfluentialHashimoto, T., Horikawa, D. D., Saito, Y., Kuwahara, H., Kozuka-Hata, H., Shin-I, T., Minakuchi, Y., Ohishi, K., Motoyama, A., Aizu, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12808 · Cited by 394 · see citing works
Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer
Liu, G., Pei, F., Yang, F., Li, L., Amin, A. D., Liu, S., Buchan, J. R., & Cho, W. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020367 · Cited by 424 · see citing works
“Following stress, p53 translocates to the nucleus and promotes sestrin1 and sestrin2 transcription and expression, which can act through AMPK-TSC2-mTOR pathway to stimulate autophagy [58].”
BackgroundSperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates
Molaro, A., Hodges, E. C., Fang, F., Song, Q., McCombie, W. R., Hannon, G. J., & Smith, A. D. (2011) · Cell · doi:10.1016/j.cell.2011.08.016 · Cited by 418 · see citing works
Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System
Kocatürk, N. M., & Gözüaçık, D. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00128 · Cited by 415 · see citing works
Free Radicals in Cross Talk Between Autophagy and Apoptosis
Kaminskyy, V. O., & Zhivotovsky, B. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5746 · Cited by 409 · see citing works
“Transcriptionally active p53 could be a potential mediator of autophagy through Sesn1/2-dependent phosphorylation of the AMPK a subunit that promotes phosphorylation of TSC2, leading to inactivation of mTORC1 (14).”
The tuberous sclerosis complex
Orlova, K. A., & Crino, P. B. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05117.x · Cited by 405 · see citing works
Roles of Autophagy in Oxidative Stress
Yun, H. R., Jo, Y. H., Kim, J., Shin, Y., Kim, S. S., & Choi, T. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093289 · Cited by 403 · see citing works
“Moreover, p53-induced Sestrin1 and Sestrin2 persuade autophagy via the activation of AMPK, thereby inhibiting mTORC1 [153].”
BackgroundDNA damage checkpoints in stem cells, ageing and cancer
Sperka, T., Wang, J., & Rudolph, K. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3420 · Cited by 393 · see citing works
Nuclear DNA damage signalling to mitochondria in ageing
Fang, E. F., Scheibye-Knudsen, M., Chua, K. F., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.14 · Cited by 387 · see citing works
AMPK As a Metabolic Tumor Suppressor: Control of Metabolism and Cell Growth
Luo, Z., Zang, M., & Guo, W. (2010) · Future Oncology · doi:10.2217/fon.09.174 · Cited by 383 · see citing works
“A second study has revealed that two downstream targets of p53, sestrin 1 and sestrin 2, are implicated in the activation of AMPK and concordant inhibition of mTOR [52].”
BackgroundLacroix, M., Riscal, R., Arena, G., Linares, L. K., & Cam, L. L. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.10.002 · Cited by 367 · see citing works
FoxOs Inhibit mTORC1 and Activate Akt by Inducing the Expression of Sestrin3 and Rictor
Chen, C.-C., Jeon, S., Bhaskar, P. T., Nogueira, V., Sundararajan, D., Tonic, I., Park, Y., & Hay, N. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.03.008 · Cited by 369 · see citing works
“Like Sesn1 and Sesn2, Sesn3 elevates the activity of AMPK.”
InfluentialModulation of intracellular ROS levels by TIGAR controls autophagy
Bensaad, K., Cheung, E. C., & Vousden, K. H. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.242 · Cited by 361 · see citing works
The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein
Feng, Z., & Levine, A. J. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.03.004 · Cited by 359 · see citing works
Maddocks, O. D. K., & Vousden, K. H. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0735-5 · Cited by 359 · see citing works
“Genotoxic stress causes p53-dependent suppression of mTOR activity via AMPK and TSC1/TSC2, leading to the suggestion that AMPK is phosphorylated in response to p53 activation, potentially via the interaction of p53 with the AMPK-activating protein LKB1 [50].”
BackgroundInfluentialDevelopment of protein kinase activators: AMPK as a target in metabolic disorders and cancer
Fogarty, S., & Hardie, D. G. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.09.012 · Cited by 351 · see citing works
Metabolic Reprogramming in Glioma
Strickland, M., & Stoll, E. A. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00043 · Cited by 350 · see citing works
“By interacting with pathways such as PI3K and mTOR, p53 is also able to limit HIF complex stabilization, resulting vascularization and migration (Budanov and Karin, 2008).”
BackgroundInfluentialAutophagy is a therapeutic target in anticancer drug resistance
Chen, S., Rehman, S. K., Zhang, W., Wen, A., Yao, L., & Zhang, J. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.07.003 · Cited by 340 · see citing works
“AMPK activates under the energy stress conditions with increased AMP/ATP ratio to repress mTOR and initiate autophagy [67].”
BackgroundSestrins Orchestrate Cellular Metabolism to Attenuate Aging
Lee, J. H., Budanov, A. V., & Karin, M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.018 · Cited by 339 · see citing works
“Consequently, Sestrin-deficient cells and tissues exhibit lower AMPK and higher mTORC1 activities under both normal and stressed conditions (Budanov and Karin, 2008; Lee et al., 2010; Wempe et al., 2010).”
InfluentialSelf-citationSestrins inhibit mTORC1 kinase activation through the GATOR complex
Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K.-L., Karin, M., & Budanov, A. V. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.019 · Cited by 336 · see citing works
“Sestrins Interact with GATOR2 We have shown that the Sestrins inhibit mTORC1 in human cancer cell lines and inDrosophila in an AMPK- and TSC-dependent manner (Budanov and Karin, 2008; Lee et al., 2010).”
BackgroundMethodInfluentialSelf-citationLiu, C.-Y., Zhang, Y.-H., Li, R., Zhou, L., An, T., Zhang, R., Zhai, M., Huang, Y. H., Yan, K., Dong, Y.-H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02280-y · Cited by 330 · see citing works
Interplay between FOXO, TOR, and Akt
Hay, N. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.03.013 · Cited by 311 · see citing works
mTOR and the control of whole body metabolism
Polak, P., & Hall, M. N. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.01.024 · Cited by 308 · see citing works
Growing knowledge of the mTOR signaling network
Huang, K., & Fingar, D. C. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.09.011 · Cited by 301 · see citing works
Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth
Rocha, G. Z., Dias, M. M., Ropelle, E. R., Osório–Costa, F., Rossato, F. A., Vercesi, A. E., Saad, M. J. A., & Carvalheira, J. B. C. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2243 · Cited by 305 · see citing works
Cellular stress response pathways and ageing: intricate molecular relationships
Kourtis, N., & Tavernarakis, N. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.162 · Cited by 304 · see citing works
“TOR (mTOR) signalling in response to genotoxic stress through a pathway that involves p53, adenosine monophosphate-activated protein kinase (AMPK) and tuberous sclerosis complex 2 (TSC2) (Budanov and Karin, 2008).”
BackgroundTumor suppressor p53 and metabolism
Liu, J., Zhang, C., Hu, W., & Feng, Z. (2018) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjy070 · Cited by 298 · see citing works
“p53 was also reported to transcriptionally induce Sestrin 1/2 to activate AMPK, which negatively regulates mTORC1 activity, leading to the inhibition of glycolysis in cells (Budanov and Karin, 2008).”
BackgroundAmino acid-dependent control of mTORC1 signaling: a variety of regulatory modes
Takahara, T., Amemiya, Y., Sugiyama, R., Maki, M., & Shibata, H. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00679-2 · Cited by 300 · see citing works
“An earlier study suggested that p53mediated induction of SESN1/2 by genotoxic stress inhibits mTORC1 through the activation of the AMPactivated protein kinase (AMPK) and TSC2 [108].”
BackgroundThe IKK complex contributes to the induction of autophagy
Criollo, A., Senovilla, L., Authier, H., Maiuri, M. C., Morselli, E., Vitale, I., Kepp, O., Tasdemir, E., Galluzzi, L., Shen, S., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.364 · Cited by 296 · see citing works
“…Biology Organization The EMBO Journal VOL 29 | NO 3 | 2010 EMBO THE JOURNAL 619 autophagic inducers such as DRAM and SESN2 (Crighton et al, 2006; Budanov and Karin, 2008), yet can repress autophagy at the cytoplasmic level through a transcription- independent mechanism (Tasdemir et al,…”
BackgroundThe lysosome as a command-and-control center for cellular metabolism
Lim, C.-Y., & Zoncu, R. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201607005 · Cited by 274 · see citing works
“Sestrin-2, a member of the Sestrin family of stress-responsive proteins (Budanov and Karin, 2008), has been shown to be a specific sensor for leucine in mammalian cells (Saxton et al.”
BackgroundA sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging
Lanna, A., Gomes, D. C. O., Muller-Durovic, B., McDonnell, T., Escors, D., Gilroy, D. W., Lee, J. H., Karin, M., & Akbar, A. N. (2017) · Nature Immunology · doi:10.1038/ni.3665 · Cited by 284 · see citing works
Self-citationMaintenance of metabolic homeostasis by Sestrin2 and Sestrin3
Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H.-W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.004 · Cited by 295 · see citing works
“Once induced, the Sestrins potentiate AMPK activation and thereby enhance phosphorylation of tuberous sclerosis complex 2 (TSC2), which in turn attenuates mTORC1 activation and stimulates autophagy (Budanov and Karin, 2008; Maiuri et al., 2009).”
BackgroundMethodInfluentialSelf-citationKim, M., Bae, S. H., Ryu, J., Kwon, Y., Oh, J.-H., Kwon, J., Moon, J., Kim, K., Miyawaki, A., Lee, M. G., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1183081 · Cited by 286 · see citing works
Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis
Wang, S., & Wang, Y. (2013) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2013.07.003 · Cited by 283 · see citing works
“Treatment of human cancer cells with YW3-56 induces the expression of SESN2, a recently identified p53 target gene that serves as an upstream inhibitor of the mTORC1-signaling pathway [22,135,136].”
BackgroundTargeting 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
“p53 can also promote the expression of Sestrins 1/2 that bind the major metabolic regulator adenosine monophosphate-activated kinase (AMPK) and TSC1/2 leading to GAP inhibitor activity and reduced mTOR function [71].”
BackgroundChaabane, W., User, S. D., El-Gazzah, M., Jaksik, R., Sajjadi, E., Rzeszowska‐Wolny, J., & Łoś, M. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0205-y · Cited by 281 · see citing works
The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.
Korotchkina, L. G., Leontieva, O. V., Bukreeva, E. I., Demidenko, Z. N., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100160 · Cited by 278 · see citing works
“In agreement with previous reports [18-20], we found that p53 inhibited the mTOR pathway [17].”
ResultThe regulation of muscle mass by endogenous glucocorticoids
Braun, T. P., & Marks, D. L. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00012 · Cited by 273 · see citing works
The Role of p53 in Metabolic Regulation
Puzio-Kuter, A. M. (2011) · Genes & Cancer · doi:10.1177/1947601911409738 · Cited by 273 · see citing works
“Furthermore, p53 up-regulates the expression of 2 target genes, sestrin 1 and sestrin 2, both of which activate AMPK, allowing AMPK to phosphorylate TSC2, which stimulates its GTPase activity to negatively regulate Rheb, the protein that activates mTOR complex 1 (mTORC1).(32) mTORC1 can also directly or indirectly dep…”
BackgroundParadoxical suppression of cellular senescence by p53
Demidenko, Z. N., Korotchkina, L. G., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002298107 · Cited by 273 · see citing works
Goul, C., Peruzzo, R., & Zoncu, R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00641-8 · Cited by 269 · see citing works
“By mining cancer genome sequence databases, 33 novel mTOR-activating mutations were discovered, mostly clustered in the C-terminal FAT and PIKK domains 191 .”
BackgroundInfluential
- Authors
- Budanov, A. V., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Karin, Michael
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 134
- Issue
- 3
- Pages
- 451-460
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2758522
- OpenAlex
- W1972618720
- Cited by
- 1,326
- References
- 50
- Citations by year
- 2026: 31 · 2025: 56 · 2024: 60 · 2023: 56 · 2022: 86 · 2021: 94 · 2020: 110 · 2019: 85 · 2018: 81 · 2017: 85 · 2016: 87 · 2015: 78 · 2014: 85 · 2013: 71 · 2012: 89
- FWCI
- 23.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1847 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- National Institute of Environmental Health Sciences (P42ES010337, 5R01 ES0637, R37ES004151, R01ES006376)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- p53, Sestrin2, mTOR signaling, TSC2, TSC1/TSC2 complex, AMPK, genotoxic stress, oxidative stress, p53 target genes, cell growth regulation, tumor suppression
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Sestrins, Animals, Cell Line, DNA Damage, Humans, Mice, Inbred C57BL, Multienzyme Complexes, Nuclear Proteins, Peroxidases, Proteins, Signal Transduction, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases
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