p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling (Cell, 2008, 134:451-460)

報告日期: 2009/03/27
報告時間: 15:10/16:00
報告學生: 林秀冠
講評老師: 張敏政


p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling

Cell 2008 Aug 8;134(3):451-60

Speaker : 林秀冠

Commentator : 張敏政 老師

Date : 2009-03-27, 15:10-16:00

Room : 602



The p53 tumor suppressor gene is a key regulator of cell cycle checkpoints and apoptosis after genotoxic stress through induction of specific target gene1. Cell growth and survival is regulated by the mammalian target of rapamycin (mTOR), which is one component of the mTORC1 complex and whose activity is inhibited by the TSC1:TSC2 complex. Many studies had shown that mTORC1 activity is inhibited by different insults such as nutrient limitation, hypoxia and DNA damage2. In author’s previous studies, they found the expression of Sestrin1(Sesn1) and Sestrin2(Sesn2), both were p53 target genes, was induced upon DNA damage and oxidative stress3. In this paper, authors tried to delineate the relationship between p53-regulated Sesn1 /Sens2 expression and mTOR signaling after genotoxic stress. They demonstrated that overexpression of Sesn1 and Sesn2, inhibited mTOR-dependent signaling downstream S6K and 4E-BP1 phosphorylation and uptstream of Rheb to TSC1:TSC2 comptex. Inhibition of mTOR by Sesn1 and Sesn2 were through the AMP-responsive protein kinase (AMPK) induced TSC2 phosphorylation. Moreover, Sesn2 deficient mice failed to inhibit mTOR signaling upon genotoxic stress. Taken these data together, the authors demonstrated that p53 is activated and leads to Sens1 and Sens2 expression upon genotoxic stress. Sens1 and Sens2 then negatively regulate mTOR signaling through activation of AMPK and TSC2 phosphorylation. Hence, Sesn1 and Sesn2 link between genotoxic stress, p53 and the mTOR signaling are suggested.


References :

1.   Vousden, K.H., and Lane, D.P. (2007). Nat. Rev.Mol. Cell Biol. 8, 275–283.

2.   Feng, Z., Hu, W., de Stanchina, E., et al. (2007). Cancer Res. 67, 3043–3053.

3.   Budanov, A.V., Sablina, A.A., et al., (2004). Science 304, 596–600.