Alternative titles; symbols
HGNC Approved Gene Symbol: SESN1
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:108,984,309-109,094,846 (from NCBI)
Transcriptional activation of target genes is a major function of p53 (191170). Using differential cDNA subtraction to identify genes activated by p53, Buckbinder et al. (1994) identified a cDNA encoding A26. Northern blot analysis revealed expression of approximately 3.0- and 4.0-kb A26 transcripts in an osteosarcoma cell line.
Velasco-Miguel et al. (1999) further characterized A26, which they called PA26. Northern blot analysis detected wide expression of the 2.6- and 4.0-kb PA26 transcripts in adult tissues. Only the smaller transcript was transiently induced by p53 or by genotoxic agents in a p53-dependent manner in a colon carcinoma cell line. By cDNA library screening and 5-prime RACE, Velasco-Miguel et al. (1999) isolated cDNAs encoding 3 PA26 variants, T1, T2, and T3, which differ at their N termini. The deduced proteins, which are 99% identical to the mouse proteins, contain 551, 491, and 426 amino acids, respectively. RT-PCR analysis detected induction of T2 in response to p53 or genotoxic stress; however, T1 was not induced and T3 was only weakly induced. Western blot analysis showed induction of a predominant 55-kD T2 nuclear protein rather than the 68-kD T1 protein or the 48-kD T3 protein. Sequence analysis predicted, and EMSA and reporter analysis confirmed, that PA26 has a p53-binding site within intron 2. Serum starvation experiments suggested that PA26 may be a member of the growth arrest- and DNA damage-inducible, or GADD, gene family (e.g., GADD45G; 604949). Velasco-Miguel et al. (1999) concluded that PA26, like GADD45, is a p53 target gene and a member of the GADD family.
By genomic sequence analysis, Velasco-Miguel et al. (1999) determined that the PA26 gene contains at least 12 exons and spans more than 20 kb.
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 (SESN2; 607767) 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.
Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK; 602739), and inhibit activation of TOR (mTOR; 601231). Lee et al. (2010) showed that the abundance of Drosophila sestrin is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun N-terminal kinase (see 601158) and transcription factor Forkhead box O (FoxO; see 136533). Loss of Drosophila Sesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacologic activation of AMPK or inhibition of TOR. Hence, Lee et al. (2010) concluded that Drosophila Sesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.
Cangelosi et al. (2022) showed that Sesn1 and Sesn2 knockout mice cannot control the rapamycin complex-1 (mTORC1) kinase response to leucine and exhibit rapid loss of white adipose tissue when fed a leucine-free diet. The authors concluded that sestrins are physiologic leucine sensors.
Using somatic cell hybrid and FISH analyses, Velasco-Miguel et al. (1999) mapped the PA26 gene to 6q21, a region associated with deletions in a number of cancers.
In a patient with heterotaxia and a de novo reciprocal translocation, t(6;18)(q21;q21), as reported by Kato et al. (1996) (see 606325), Peeters et al. (2003) found that the PA26 gene was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line from this patient. Mutation analysis of the PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia.
Buckbinder, L., Talbott, R., Seizinger, B. R., Kley, N. Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes. Proc. Nat. Acad. Sci. 91: 10640-10644, 1994. [PubMed: 7938006] [Full Text: https://doi.org/10.1073/pnas.91.22.10640]
Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V., Chumakov, P. M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304: 596-600, 2004. [PubMed: 15105503] [Full Text: https://doi.org/10.1126/science.1095569]
Cangelosi, A. L., Puszynska, A. M., Roberts, J. M., Armani, A., Nguyen, T. P., Spinelli, J. B., Kunchok, T., Wang, B., Chan, S. H., Lewis, C. A., Comb, W. C., Bell, G. W., Helman, A., Sabatini, D. M. Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine. Science 377: 47-56, 2022. [PubMed: 35771919] [Full Text: https://doi.org/10.1126/science.abi9547]
Kato, R., Yamada, Y., Niikawa, N. De novo balanced translocation (6;18)(q21;q21.3) in a patient with heterotaxia. Am. J. Med. Genet. 66: 184-186, 1996. Note: Erratum: Am. J. Med. Genet. 70: 104 only, 1997. [PubMed: 8958327] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2<184::AID-AJMG11>3.0.CO;2-P]
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. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327: 1223-1228, 2010. [PubMed: 20203043] [Full Text: https://doi.org/10.1126/science.1182228]
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. 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, 2003. [PubMed: 12607115] [Full Text: https://doi.org/10.1007/s00439-003-0917-5]
Velasco-Miguel, S., Buckbinder, L., Jean, P., Gelbert, L., Talbott, R., Laidlaw, J., Seizinger, B., Kley, N. 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, 1999. [PubMed: 9926927] [Full Text: https://doi.org/10.1038/sj.onc.1202274]