Skip to main content
SpringerLink
Log in

Sestrins are Gatekeepers in the Way from Stress to Aging and Disease

  • REVIEWS
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract—

Sestrins belong to a family of evolutionary conserved proteins which are found in the majority of animal species. While invertebrate genomes contain only one sestrin gene, mammalian and other vertebrate genomes comprise three highly homologous genes that encode Sestrin 1, 2 and 3 proteins (Sesn1, Sesn2 and Sesn3). Sestrins are activated in response to a variety of stimuli and trigger metabolic shifts promoting cell survival under stress conditions. Although cellular stress within an organism is often caused by external stimuli it can be induced by excess of cytokines, chemokines, reactive oxygen species which are produced during aberrant metabolic or immune processes and are involved in regulation of cell physiological states including cell death. Activation of sestrins facilitates cell adaptation to stress through stimulation of antioxidant response and autophagy through regulation of the signaling pathways mediated by AMPK and mTOR kinases. These activities are involved in protection of the organism during physical exercise and certain level of sestrins activity contributes to the development of age-related diseases. However, prolonged activation of sestrins under chronic stress may cause negative effects for the organism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

REFERENCES

  1. Velasco-Miguel S., Buckbinder L., Jean P., Gelbert L., Talbott R., Laidlaw J., Seizinger B., Kley N. 1999. PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene. 18, 127–137.

    Article  CAS  PubMed  Google Scholar 

  2. Budanov A.V., Shoshani T., Faerman A., Zelin E., Kamer I., Kalinski H., Gorodin S., Fishman A., Chajut A., Einat P., Skaliter R., Gudkov A.V., Chumakov P.M., Feinstein E. 2002. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene. 21, 6017–6031.

    Article  CAS  PubMed  Google Scholar 

  3. Peeters H., Debeer P., Bairoch A., Wilquet V., Huysmans C., Parthoens E., Fryns J.P., Gewillig M., Nakamura Y., Niikawa N., van de Ven W., Devriendt K. 2003. PA26 is a candidate gene for heterotaxia in humans: Identification of a novel PA26-related gene family in human and mouse. Hum. Genet. 112, 573–580.

    CAS  PubMed  Google Scholar 

  4. Budanov A.V., Lee J.H., Karin M. 2010. Stressin’ Sestrins take an aging fight. EMBO Mol. Med. 2, 388–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen C.C., Jeon S.M., Bhaskar P.T., Nogueira V., Sundararajan D., Tonic I., Park Y., Hay N. 2010. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev. Cell. 18, 592–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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., Karin M. 2010. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 327, 1223–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolfson R.L., Sabatini D.M. 2017. The Dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 26, 301–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Budanov A.V., Sablina A.A., Feinstein E., Koonin E.V., Chumakov P.M. 2004. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 304, 596–600.

    Article  CAS  PubMed  Google Scholar 

  9. Bryk R., Lima C.D., Erdjument-Bromage H., Tempst P., Nathan C. 2002. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 295, 1073–1077.

    Article  CAS  PubMed  Google Scholar 

  10. Wolfson R.L., Chantranupong L., Saxton R.A., Shen K., Scaria S.M., Cantor J.R., Sabatini D.M. 2016. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 351, 43–48.

    Article  CAS  PubMed  Google Scholar 

  11. Kim H., An S., Ro S.H., Teixeira F., Park G.J., Kim C., Cho C.S., Kim J.S., Jakob U., Lee J.H., Cho U.S. 2015. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat. Commun. 6, 1–11.

    Google Scholar 

  12. Kimball S.R., Gordon B.S., Moyer J.E., Dennis M.D., Jefferson L.S. 2016. Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal. 28, 896–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Budanov A.V. 2011. Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid. Redox Signal. 15, 1679–1690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kruiswijk F., Labuschagne C.F., Vousden K.H. 2015. p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393–405.

    Article  CAS  Google Scholar 

  15. Wei C.L., Wu Q., Vega V.B., Chiu K.P., Ng P., Zhang T., Shahab A., Yong H.C., Fu Y., Weng Z., Liu J., Zhao X.D., Chew J.L, Lee Y.L., Kuznetsov V.A., et al. 2006. A global map of p53 transcription-factor binding sites in the human genome. Cell. 124, 207–219.

    Article  CAS  PubMed  Google Scholar 

  16. Ben-Sahra I., Dirat B., Laurent K., Puissant A., Auberger P., Budanov A., Tanti J.F., Bost F. 2013. Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death. Cell Death Differ. 20, 611–619.

    Article  CAS  PubMed  Google Scholar 

  17. Ding B., Parmigiani A., Divakaruni A.S., Archer K., Murphy A.N., Budanov A.V. 2016. Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death. Sci. Rep. 6, 22538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parmigiani A., Budanov A.V. 2016. Sensing the environment through Sestrins: implications for cellular metabolism. Int. Rev. Cell. Mol. Biol. 327, 1–42.

    Article  CAS  PubMed  Google Scholar 

  19. Ye J., Palm W., Peng M., King B., Lindsten T., Li M.O., Koumenis C., Thompson C.B. 2015. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 29, 2331–2336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jegal K.H., Park S.M., Cho S.S., Byun S.H., Ku S.K., Kim S.C., Ki S.H., Cho I.J. 2017. Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury. Biochim. Biophys. Acta. 1864, 1295–1307.

    Article  CAS  Google Scholar 

  21. Byun J.K., Choi Y.K., Kim J.H., Jeong J.Y., Jeon H.J., Kim M.K., Hwang I., Lee S.Y., Lee Y.M., Lee I.K., Park K.G. 2017. A positive feedback loop between Sestrin2 and mTORC2 is required for the survival of glutamine-depleted lung cancer cells. Cell Rep. 20, 586–599.

    Article  CAS  PubMed  Google Scholar 

  22. Walter P., Ron D. 2011. The unfolded protein response: From stress pathway to homeostatic regulation. Science. 334, 1081–1086.

    Article  CAS  PubMed  Google Scholar 

  23. Nogueira V., Park Y., Chen C.C., Xu P.Z., Chen M.L., Tonic I., Unterman T., Hay N. 2008. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 14, 458–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hagenbuchner J., Kuznetsov A., Hermann M., Hausott B., Obexer P., Ausserlechner M.J. 2012. FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J. Cell Sci. 125, 1191–1203.

    Article  CAS  PubMed  Google Scholar 

  25. Eijkelenboom A., Burgering B.M. 2013. FOXOs: Signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 14, 83–97.

    Article  CAS  PubMed  Google Scholar 

  26. Saxton R.A., Sabatini D.M. 2017. mTOR signaling in growth, metabolism, and disease. Cell. 169, 361–371.

    Article  CAS  PubMed  Google Scholar 

  27. Wullschleger S., Loewith R., Hall M.N. 2006. TOR signaling in growth and metabolism. Cell. 124, 471–484.

    Article  CAS  PubMed  Google Scholar 

  28. Mizushima N. 2007. Autophagy: Process and function. Genes Dev. 21, 2861–2873.

    Article  CAS  PubMed  Google Scholar 

  29. Settembre C., Fraldi A., Medina D.L., Ballabio A. 2013. Signals from the lysosome: A control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Manning B.D., Toker A. 2017. AKT/PKB signaling: Navigating the network. Cell. 169, 381–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sancak Y., Peterson T.R., Shaul Y.D., Lindquist R.A., Thoreen C.C., Bar-Peled L., Sabatini D.M. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 320, 1496–1501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bar-Peled L., Chantranupong L., Cherniack A.D., Chen W.W., Ottina K.A., Grabiner B.C., Spear E.D., Carter S.L., Meyerson M., Sabatini D.M. 2013. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 340, 1100–1106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Peng M., Yin N., Li M.O. 2017. SZT2 dictates GATOR control of mTORC1 signalling. Nature. 543, 433–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wolfson R.L., Chantranupong L., Wyant G.A., Gu X., Orozco J.M., Shen K., Condon K.J., Petri S., Kedir J., Scaria S.M., Abu-Remaileh M., Frankel W.N., Sabatini D.M. 2017. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature. 543, 438–442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Budanov A.V., Karin M. 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 134, 451–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Morrison A., Chen L., Wang J., Zhang M., Yang H., Ma Y., Budanov A., Lee J.H., Karin M., Li J. 2015. Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart. FASEB J. 29, 408–417.

    Article  CAS  PubMed  Google Scholar 

  37. Parmigiani A., Nourbakhsh A., Ding B., Wang W., Kim Y.C., Akopiants K., Guan K.L., Karin M., Budanov A.V. 2014. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9, 1281–1291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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. The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Saxton R.A., Knockenhauer K.E., Wolfson R.L., Chantranupong L., Pacold M.E., Wang T., Schwartz T.U., Sabatini D.M. 2016. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 351, 53–58.

    Article  CAS  PubMed  Google Scholar 

  40. 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., Wolfe A.M., Perkins G.A., Ellisman M.H., Bier E., Scadeng M., Foretz M., et al. 2012. Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 16, 311–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao B., Shah P., Budanov A.V., Qiang L., Ming M., Aplin A., Sims D.M., He Y.Y. 2014. Sestrin2 protein positively regulates AKT enzyme signaling and survival in human squamous cell carcinoma and melanoma cells. J. Biol. Chem. 289, 35806–35814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tao R., Xiong X., Liangpunsakul S., Dong X.C. 2015. Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling. Diabetes. 64, 1211–1223.

    Article  CAS  PubMed  Google Scholar 

  43. Woo H.A., Bae S.H., Park S., Rhee S.G. 2009. Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid. Redox Signal. 11, 739–745.

    Article  CAS  PubMed  Google Scholar 

  44. Green D.R., Galluzzi L., Kroemer G. 2011. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 333, 1109–1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li D.D., Sun T., Wu X.Q., Chen S.P., Deng R., Jiang S., Feng G.K., Pan J.X., Zhang X.S., Zeng Y.X., Zhu X.F. 2012. The inhibition of autophagy sensitises colon cancer cells with wild-type p53 but not mutant p53 to topotecan treatment. PLoS One. 7, e45058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Saveljeva S., Cleary P., Mnich K., Ayo A., Pakos-Zebrucka K., Patterson J.B., Logue S.E., Samali A. 2016. Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival. Oncotarget. 7, 12254–12266.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Scheibye-Knudsen M., Fang E.F., Croteau D.L., Wilson D.M., Bohr V.A. 2015. Protecting the mitochondrial powerhouse. Trends Cell Biol. 25, 158–170.

    Article  CAS  PubMed  Google Scholar 

  48. Kim M.J., Bae S.H., Ryu J.C., Kwon Y., Oh J.H., Kwon J., Moon J.S., Kim K., Miyawaki A., Lee M.G., Shin J., Kim Y.S., Kim C.H., Ryter S.W., Choi A.M., et al. 2016. SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy. 12, 1272–1291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bae 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. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. 17, 73–84.

    Article  CAS  PubMed  Google Scholar 

  50. Tomasovic A., Kurrle N., Surun D., Heidler J., Husnjak K., Poser I., Schnutgen F., Scheibe S., Seimetz M., Jaksch P., Hyman A., Weissmann N., von Melchner H. 2015. Sestrin 2 protein regulates platelet-derived growth factor receptor beta (Pdgfrbeta) expression by modulating proteasomal and Nrf2 transcription factor functions. J. Biol. Chem. 290, 9738–9752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu S.Y., Lee Y.J., Lee T.C. 2011. Association of platelet-derived growth factor receptor beta accumulation with increased oxidative stress and cellular injury in sestrin 2 silenced human glioblastoma cells. FEBS Lett. 585, 1853–1858.

    Article  CAS  PubMed  Google Scholar 

  52. Eid A.A., Lee D.Y., Roman L.J., Khazim K., Gorin Y. 2013. Sestrin 2 and AMPK connect hyperglycemia to Nox4-dependent endothelial nitric oxide synthase uncoupling and matrix protein expression. Mol. Cell Biol. 33, 3439–3460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Brace L.E., Vose S.C., Stanya K., Gathungu R.M., Marur V.R., Longchamp A., Trevino-Villarreal H., Mejia P., Vargas D., Inouye K., Bronson R.T., Lee C.H., Neilan E., Kristal B.S., Mitchell J.R. 2016. Increased oxidative phosphorylation in response to acute and chronic DNA damage. NPJ Aging Mech. Dis. 2, 16022.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Garaeva A.A., Kovaleva I.E., Chumakov P.M., Evstafieva A.G. 2016. Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4. Cell Cycle. 15, 64–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hou Y.S., Guan J.J., Xu H.D., Wu F., Sheng R., Qin Z.H. 2015. Sestrin2 protects dopaminergic cells against rotenone toxicity through AMPK-dependent autophagy activation. Mol. Cell Biol. 35, 2740–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bruning A., Rahmeh M., Friese K. 2013. Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation. Mol. Oncol. 7, 1012–1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sanli T., Linher-Melville K., Tsakiridis T., Singh G. 2012. Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cells. PLoS One. 7, e32035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ding B., Parmigiani A., Yang C., Budanov A.V. 2015. Sestrin2 facilitates death receptor-induced apoptosis in lung adenocarcinoma cells through regulation of XIAP degradation. Cell Cycle. 14, 3231–3241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lopez-Otin C., Blasco M.A., Partridge L., Serrano M., Kroemer G. 2013. The hallmarks of aging. Cell. 153, 1194–1217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cornu M., Albert V., Hall M.N. 2013. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62.

    Article  CAS  PubMed  Google Scholar 

  61. Johnson S.C., Rabinovitch P.S., Kaeberlein M. 2013. mTOR is a key modulator of ageing and age-related disease. Nature. 493, 338–345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kourtis N., Tavernarakis N. 2011. Cellular stress response pathways and ageing: Intricate molecular relationships. EMBO J. 30, 2520–2531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang Y.L., Loh K.S., Liou B.Y., Chu I.H., Kuo C.J., Chen H.D., Chen C.S. 2013. SESN-1 is a positive regulator of lifespan in Caenorhabditis elegans. Exp. Gerontol. 48, 371–379.

    Article  CAS  PubMed  Google Scholar 

  64. Lee J.H., Budanov A.V., Karin M. 2013. Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab. 18, 792–801.

    Article  CAS  PubMed  Google Scholar 

  65. Park H.W., Park H., Ro S.H., Jang I., Semple I.A., Kim D.N., Kim M., Nam M., Zhang D., Yin L., Lee J.H. 2014). Hepatoprotective role of Sestrin2 against chronic ER stress. Nat. Commun. 5, 4233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Quan N., Sun W., Wang L., Chen X., Bogan J.S., Zhou X., Cates C., Liu Q., Zheng Y., Li J. 2017. Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J. 31, 4153–4167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hwang H.J., Jung T.W., Choi J.H., Lee H.J., Chung H.S., Seo J.A., Kim S.G., Kim N.H., Choi K.M., Choi D.S., Baic S.H., Yoo H.J. 2017. Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism. Biochim. Biophys. Acta. 1863, 1436–1444.

    Article  CAS  Google Scholar 

  68. Yang J.H., Kim K.M., Kim M.G., Seo K.H., Han J.Y., Ka S.O., Park B.H., Shin S.M., Ku S.K., Cho I.J., Ki S.H. 2015. Role of sestrin2 in the regulation of proinflammatory signaling in macrophages. Free Radic. Biol. Med. 78, 156–167.

    Article  CAS  PubMed  Google Scholar 

  69. Kim M.G., Yang J.H., Kim K.M., Jang C.H., Jung J.Y., Cho I.J., Shin S.M., Ki S.H. 2015. Regulation of Toll-like receptor-mediated Sestrin2 induction by AP-1, Nrf2, and the ubiquitin-proteasome system in macrophages. Toxicol. Sci. 144, 425–435.

    Article  CAS  PubMed  Google Scholar 

  70. Yang K., Xu C., Zhang Y., He S., Li D. 2017. Sestrin2 suppresses classically activated macrophages-mediated inflammatory response in myocardial infarction through inhibition of mTORC1 signaling. Front. Immunol. 8, 728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen Y.S., Chen S.D., Wu C.L., Huang S.S., Yang D.I. 2014. Induction of sestrin2 as an endogenous protective mechanism against amyloid beta-peptide neurotoxicity in primary cortical culture. Exp. Neurol. 253, 63–71.

    Article  CAS  PubMed  Google Scholar 

  72. Kim J.R., Lee S.R., Chung H.J., Kim S., Baek S.H., Kim J.H., Kim Y.S. 2003. Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: Involvement of RTP801 in amyloid beta-peptide toxicity. Exp. Mol. Med. 35, 403–411.

    Article  CAS  PubMed  Google Scholar 

  73. Reddy K., Cusack C.L., Nnah I.C., Khayati K., Saqcena C., Huynh T.B., Noggle S.A., Ballabio A., Dobrowolski R. 2016. Dysregulation of nutrient sensing and CLEARance in presenilin deficiency. Cell Rep. 14, 2166–2179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhou D., Zhan C., Zhong Q., Li S. 2013. Upregulation of sestrin-2 expression via P53 protects against 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity. J. Mol. Neurosci. 51, 967–975.

    Article  CAS  PubMed  Google Scholar 

  75. Papadia S., Soriano F.X., Leveille F., Martel M.A., Dakin K.A., Hansen H.H., Kaindl A., Sifringer M., Fowler J., Stefovska V., McKenzie G., Craigon M., Corriveau R., Ghazal P., Horsburgh K., et al. 2008. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat. Neurosci. 11, 476–487.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kallenborn-Gerhardt W., Lu R., Syhr K.M., Heidler J., von Melchner H., Geisslinger G., Bangsow T., Schmidtko A. 2013. Antioxidant activity of sestrin 2 controls neuropathic pain after peripheral nerve injury. Antioxid. Redox Signal. 19, 2013–2023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Johnson M.R., Behmoaras J., Bottolo L., Krishnan M.L., Pernhorst K., Santoscoy P.L.M., Rossetti T., Speed D., Srivastava P.K., Chadeau-Hyam M., Hajji N., Dabrowska A., Rotival M., Razzaghi B., Kovac S., et al. 2015. Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nat. Commun. 6, 6031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yeh S.H., Chen P.J., Chen H.L., Lai M.Y., Wang C.C., Chen D.S. 1994. Frequent genetic alterations at the distal region of chromosome 1p in human hepatocellular carcinomas. Cancer Res. 54, 4188–4192.

    CAS  PubMed  Google Scholar 

  79. White P.S., Kaufman B.A., Marshall H.N., Brodeur G.M. 1993. Use of the single-strand conformation polymorphism technique to detect loss of heterozygosity in neuroblastoma. Genes Chromosomes Cancer. 7, 102–108.

    Article  CAS  PubMed  Google Scholar 

  80. Nagai H., Negrini M., Carter S.L., Gillum D.R., Rosenberg A.L., Schwartz G.F., Croce C.M. 1995. Detection and cloning of a common region of loss of heterozygosity at chromosome 1p in breast cancer. Cancer Res. 55, 1752–1757.

    CAS  PubMed  Google Scholar 

  81. Leister I., Weith A., Bruderlein S., Cziepluch C., Kangwanpong D., Schlag P., Schwab M. 1990. Human colorectal cancer: High frequency of deletions at chromosome 1p35. Cancer Res. 50, 7232–7235.

    CAS  PubMed  Google Scholar 

  82. Lehmann S., Ogawa S., Raynaud S.D., Sanada M., Nannya Y., Ticchioni M., Bastard C., Kawamata N., Koeffler H.P. 2008. Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer. 112, 1296–1305.

    Article  CAS  PubMed  Google Scholar 

  83. Thelander E.F., Ichimura K., Corcoran M., Barbany G., Nordgren A., Heyman M., Berglund M., Mungall A., Rosenquist R., Collins V.P., Grander D., Larsson C., Lagercrantz S. 2008. Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia. Leukemia Lymphoma. 49, 477–487.

    Article  CAS  PubMed  Google Scholar 

  84. Hatano N., Nishikawa N.S., McElgunn C., Sarkar S., Ozawa K., Shibanaka Y., Nakajima M., Gohiji K., Kiyama R. 2001. A comprehensive analysis of loss of heterozygosity caused by hemizygous deletions in renal cell carcinoma using a subtraction library. Mol. Carcinogen. 31, 161–170.

    Article  CAS  Google Scholar 

  85. Carvalho B., Seruca R., Buys C.H., Kok K. 2002. Novel expressed sequences obtained by means of a suppression subtractive hybridisation analysis from the 6q21 region that is frequently deleted in gastric cancer. Eur. J. Cancer. 38, 1126–1132.

    Article  CAS  PubMed  Google Scholar 

  86. Abe T., Makino N., Furukawa T., Ouyang H., Kimura M., Yatsuoka T., Yokoyama T., Inoue H., Fukushige S., Hoshi M., Hayashi Y., Sunamura M., Kobari M., Matsuno S., Horii A. 1999. Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. Genes Chromosomes Cancer. 25, 60–64.

    Article  CAS  PubMed  Google Scholar 

  87. Chen K.B., Xuan Y., Shi W.J., Chi F., Xing R., Zeng Y.C. 2016. Sestrin2 expression is a favorable prognostic factor in patients with non-small cell lung cancer. Am. J. Transl. Res. 8, 1903–1909.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wei J.L., Fu Z.X., Fang M., Guo J.B., Zhao Q.N., Lu W.D., Zhou Q.Y. 2015. Decreased expression of sestrin 2 predicts unfavorable outcome in colorectal cancer. Oncol. Rep. 33, 1349–1357.

    Article  CAS  PubMed  Google Scholar 

  89. Sablina A.A., Budanov A.V., Ilyinskaya G.V., Agapova L.S., Kravchenko J.E., Chumakov P.M. 2005. The antioxidant function of the p53 tumor suppressor. Nat. Med. 11, 1306–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ro S.H., Xue X., Ramakrishnan S.K., Cho C.S., Namkoong S., Jang I., Semple I.A., Ho A., Park H.W., Shah Y.M., Lee J.H. 2016. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis. eLife. 5, e12204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oricchio E., Katanayeva N., Donaldson M.C., Sungalee S., Pasion J.P., Beguelin W., Battistello E., Sanghvi V.R., Jiang M., Jiang Y., Teater M., Parmigiani A., Budanov A.V., Chan F.C., Shah S.P., et al. 2017. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci. Transl. Med. 9, eaak9969.

  92. Zighelboim I., Goodfellow P.J., Schmidt A.P., Walls K.C., Mallon M.A., Mutch D.G., Yan P.S., Huang T.H., Powell M.A. 2007. Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers. Clin. Cancer Res. 13, 2882–2889.

    Article  CAS  PubMed  Google Scholar 

  93. Kopnin P.B., Agapova L.S., Kopnin B.P., Chumakov P.M. 2007. Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability. Cancer Res. 67, 4671–4678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Heidler J., Fysikopoulos A., Wempe F., Seimetz M., Bangsow T., Tomasovic A., Veit F., Scheibe S., Pichl A., Weisel F., Lloyd KC., Jaksch P., Klepetko W., Weissmann N., von Melchner H. 2013. Sestrin-2, a repressor of PDGFRbeta signalling, promotes cigarette-smoke-induced pulmonary emphysema in mice and is upregulated in individuals with COPD. Dis. Model. Mech. 6, 1378–1387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wempe F., De-Zolt S., Koli K., Bangsow T., Parajuli N., Dumitrascu R., Sterner-Kock A., Weissmann N., Keski-Oja J., von Melchner H. 2010. Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD. Dis. Model. Mech. 3, 246–253.

    Article  CAS  PubMed  Google Scholar 

  96. Mizumura K., Cloonan S.M., Nakahira K., Bhashyam A.R., Cervo M., Kitada T., Glass K., Owen C.A., Mahmood A., Washko G.R., Hashimoto S., Ryter S.W., Choi A.M. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yoshida T., Mett I., Bhunia A.K., Bowman J., Perez M., Zhang L., Gandjeva A., Zhen L., Chukwueke U., Mao T., Richter A., Brown E., Ashush H., Notkin N., Gelfand A., et al. 2010. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat. Med. 16, 767–773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang C., Sun W., Li J., Xiong B., Frye M.D., Ding D., Salvi R., Kim M.J., Someya S., Hu B.H. 2017. Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea. Neuroscience. 361, 179–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ebnoether E., Ramseier A., Cortada M., Bodmer D., Levano-Huaman S. 2017. Sesn2 gene ablation enhances susceptibility to gentamicin-induced hair cell death via modulation of AMPK/mTOR signaling. Cell Death Discov. 3, 17024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lanna A., Gomes D.C., Muller-Durovic B., McDonnell T., Escors D., Gilroy D.W., Lee J.H., Karin M., Akbar A.N. 2017. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia

    A. A. Dalina & A. V. Budanov

  2. Trinity College Dublin, Dublin 2, Ireland

    A. A. Dalina & A. V. Budanov

  3. Belozersky Institute of Physical and Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    I. E. Kovaleva

Authors
  1. A. A. Dalina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. E. Kovaleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. V. Budanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. V. Budanov.

Additional information

Dedicated to Aleksandra G. Evstaf’eva, an eminent scientist and our friend, who untimely passed away in 2018

Translated by G. Chirikova

Abbreviations: AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; CDT, C-terminal domain; GAP, GTPase activating protein; LBS, leucine-binding site; mTOR, mechanistic/mammalian target of rapamycin; mTORC1/2, mTOR complex 1/2; NRF2, nuclear factor erythroid 2-related factor 2; NTD, N-terminal domain; ROS, reactive oxygen species; COPD, chronic obstructive pulmonary disease; ER, endoplasmic reticulum.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dalina, A.A., Kovaleva, I.E. & Budanov, A.V. Sestrins are Gatekeepers in the Way from Stress to Aging and Disease. Mol Biol 52, 823–835 (2018). https://doi.org/10.1134/S0026893318060043

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893318060043

Keywords:

Search

Navigation