Alternative titles; symbolsSEST2HYPOXIA-INDUCED GENE 95; HI95HGNC Approved Gene Symbol: SESN2Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,...
Alternative titles; symbols
HGNC Approved Gene Symbol: SESN2
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,259,451-28,282,490 (from NCBI)
▼ Cloning and Expression
Using a microarray-based analysis, Budanov et al. (2002) identified SEST2, which they designated HI95, as a gene upregulated in a glioma cell line maintained under hypoxic conditions for 16 hours. The full-length SEST2 cDNA encodes a deduced 480-amino acid protein predicted to be a compact globular domain protein composed predominantly of alpha-helical structures. SEST2 has several potential serine-threonine and tyrosine phosphorylation sites, most of them located within the alpha helices. Northern blot analysis revealed a 3.9-kb transcript expressed at low to moderate levels in most tissues examined. In vitro translation of the cDNA resulted in a protein with an apparent molecular mass of about 60 kD.
Peeters et al. (2003) analyzed the structure of p53 (191170)-activated gene-26 (PA26, or sestrin-1; 606103) and identified a novel PA26-related gene family, which they termed the sestrin family, comprising 3 closely related genes in human and in mouse, PA26, SEST2, and SEST3 (607768).
▼ Gene Function
In addition to observing upregulation of SEST2 following hypoxia in cultured glioma cells, Budanov et al. (2002) found SEST2 expression increased following DNA damage or oxidative stress, but not following hyperthermia or serum starvation. Induction of SEST2 by prolonged hypoxia or by oxidative stress appeared to be independent of p53 activation, but its induction following DNA damage (by gamma or ultraviolet irradiation, or by doxorubicin) occurred in a p53-dependent manner. Overexpression of SEST2 was toxic to many cultured cell types and led to apoptotic cell death or to sensitization to experimental insults. However, overexpression of SEST2 in a breast cancer cell line resulted in protection from apoptotic cell death. Budanov et al. (2002) concluded that SEST2 is involved in complex regulation of cell viability in response to different stress conditions.
Acting as a signal, hydrogen peroxide circumvents antioxidant defense by overoxidizing peroxiredoxins (Prxs), the enzymes that metabolize peroxides. Budanov et al. (2004) showed that sestrins, a family of proteins whose expression is modulated by p53, are required for regeneration of Prxs containing cys-SO(2)H, thus reestablishing the antioxidant firewall. Sestrins contain a predicted redox-active domain homologous to AhpD, the enzyme catalyzing the reduction of a bacterial peroxiredoxin, AhpC. Purified Hi95 (sestrin-2) protein supported adenosine triphosphate-dependent reduction of overoxidized PrxI in vitro, indicating that unlike AhpD, which is a disulfide reductase, sestrins are cysteine sulfinyl reductases.
Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex-1 (mTORC1; see 601231) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the RAG guanosine triphosphatases (RAG GTPases; see 612194). Several factors regulate the RAGs, including the GATOR1 complex (see 607072), a GTPase-activating protein; the pentameric protein complex GATOR2 (see 615359), which negatively regulates GATOR1; and SESN2, a GATOR2-interacting protein that inhibits mTORC1 signaling. Wolfson et al. (2016) found that leucine, but not arginine, disrupts the SESN2-GATOR2 interaction by binding to SESN2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of SESN2 is required for leucine to activate mTORC1 in cells. Wolfson et al. (2016) concluded that SESN2 is a leucine sensor for the mTORC1 pathway.
▼ Biochemical Features
Saxton et al. (2016) presented the 2.7-angstrom crystal structure of SESN2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in SESN2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. Saxton et al. (2016) concluded that these results provided a structural mechanism of amino acid sensing by the mTORC1 pathway.
Using FISH, Peeters et al. (2003) mapped the human sestrin genes PA26, SEST2, and SEST3 (607768) to chromosomes 6q21, 1p35.3, and 11q21, respectively. They mapped the mouse Pa26, Sest2, and Sest3 genes to syntenic regions on chromosomes 4, 9, and 10, respectively.