The reference OMIM entry for this protein is 606103

Sestrin 1; sesn1
Sest1
P53-activated gene 26
Pa26

CLONING

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.

GENE STRUCTURE

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.

GENE FUNCTION

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; 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 tha ... More on the omim web site

Subscribe to this protein entry history

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606103 was added.