Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 8 November 2011
Vol. 4, Issue 198, p. ec311
[DOI: 10.1126/scisignal.4198ec311]

EDITORS' CHOICE

mTORC1 Signaling Provoking Preterm Birth

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Preterm births result in an increased risk of neonatal death and developmental and learning difficulties. Many risk factors are implicated in triggering premature delivery, including inflammation, stress, genetic factors, and infection; however, the underlying mechanism(s) are unclear. Noting that many of these risk factors also contribute to cellular senescence, and that mammalian target of rapamycin complex 1 (mTORC1) signaling is associated with senescence, Hirota et al. investigated a role for mTORC1 in preterm birth in mice. The authors had previously shown that female mice with conditional deletion of p53 in the uterus (p53d/d mice) exhibit premature delivery, which is associated with increased activity of the serine and threonine kinase Akt. They also showed that preterm birth was associated with premature senescence in the decidua, the lining of the uterus during pregnancy. Under normal conditions, senescence in the decidua increases as the time of birth approaches. In the current study, the authors found that the abundance of phosphorylated S6, a downstream effector of mTORC1, was higher in p53d/d mice than in control mice during pregnancy. Administration of the mTORC1 inhibitor rapamycin to p53d/d mice during pregnancy reduced the incidence of preterm birth and neonatal death. Compared with the decidua of control mice, the decidua of p53d/d mice on day 16 of pregnancy exhibited increased senescence, a phenotype that was prevented by rapamycin. Knockout of the gene encoding p21, which promotes cell cycle arrest and senescence, rescued the preterm birth defect of p53d/d mice. The abundances of cyclooxygenase 2 (COX2) and prostaglandin F synthase (PGFS), two enzymes required for the synthesis of PGF2α, which contributes to the onset of delivery, were higher in uterine samples from p53d/d mice than in those from control mice. Loss of p21 or treatment with rapamycin reduced the amounts of COX2 and PGFS in p53d/d mice to those found in control mice. Together, these data suggest a role for mTORC1 signaling in determining the timing of birth through a mechanism that activates COX2 and increases senescence in the decidua.

Y. Hirota, J. Cha, M. Yoshie, T. Daikoku, S. K. Dey, Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc. Natl. Acad. Sci. U.S.A. 108, 18073–18078 (2011). [Abstract] [Full Text]

Citation: J. F. Foley, Provoking Preterm Birth. Sci. Signal. 4, ec311 (2011).


To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882