Abstract
Sestrins (Sesns) are a family of highly conserved stress-responsive proteins, transcriptionally regulated by p53 and forkhead transcription factor that exhibit oxidoreductase activity in vitro and can protect cells from oxidative stress. However, their major biochemical and physiological function does not appear to depend on their redox (reduction and oxidation) activity. Sesns promote activation of adenosine-5′-monophosphate (AMP)-dependent protein kinase in both mammals and flies. Stress-induced Sesn expression results in inhibition of the target of rapamycin complex 1 (TORC1) and the physiological and pathological implications of disrupting the Sesns-TORC1 crosstalk are now being unravelled. Detailing their mechanism of action and exploring their roles in human physiology point to exciting new insights to topics as diverse as stress, cancer, metabolism and aging.
Highlights
Introduction scriptionally regulated by p53 and forkhead transcription factor that exhibit oxidoreductase activity in vitro and can protect cells from oxidative stress
Since target of rapamycin complex 1 (TORC1) signalling pathway is known to be involved in obesity-induced hepatosteatosis, accumulation of white adipose tissue (WAT) and diabetic progression in mammals (Dann et al, 2007; Laplante & Sabatini, 2009a; Laplante & Sabatini, 2009b), it will be interesting to determine the role of Sesns in regulation of lipid metabolism in different metabolically active organs such as liver, adipose tissue and muscle
Sesns are evolutionarily conserved stress-inducible genes that encode antioxidant proteins involved in the regulation of the AMPK-TORC1 axis
Summary
The tumour suppressor protein p53 has attracted much attention since its identification (Lane & Crawford, 1979) and molecular cloning (Chumakov et al, 1982; Oren & Levine, 1983), mainly because the gene is mutated and/or inactivated in most human cancers (Levine, 1997). p53 protein accumulation and activity are induced by genotoxic stress (Levine, 1997) as well as oxidative (Sablina et al, 2005) and oncogenic stresses (Lowe et al, 2004). p53 is a well-established transcription factor with tumour suppressive properties as its absence in mice results in spontaneous tumours (Donehower et al, 1992). Many p53 target genes have been thoroughly characterized and implicated in its tumour suppressive functions (Vousden & Lane, 2007; Vousden & Prives, 2009), but so far not a single target gene whose ablation results in tumorogenesis has been identified. Cancer Disease featuring abnormal and uncontrolled proliferation of a group of cells resulting in invasive growths or tumour followed by spread throughout the body. Genotoxic stress Reaction of cells or organism on DNA-damage induced by genotoxins, irradiation or intrinsic inability to support DNA integrity. Lipogenesis encompasses the process of fatty acid synthesis and subsequent triglyceride synthesis It plays an important role in conservation of energy in form of fat. Parkinson’s disease Age-related neurodegenerative disease, characterized pathologically by protein aggregates in the brain, mainly composed of alphasynuclein, known as Lewy bodies. Whereas vertebrates contain three Sesn genes, invertebrates in general have a single Sesn with no Sesn genes found in yeast (Lee et al, 2010) (Fig 2)
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