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FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse
K E Hentges1, B Sirry, A C Gingeras
1Gallo Center, University of California at San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA.
Abstract:
The FKBP-12-rapamycin associated protein (FRAP, also known as mTOR and RAFT-1) is a member of the phosphoinositide kinase related kinase family. FRAP has serine/threonine kinase activity and mediates the cellular response to mitogens through signaling to p70s6 kinase (p70(s6k)) and 4E-BP1, resulting in an increase in translation of subsets of cellular mRNAs. Translational up-regulation is blocked by inactivation of FRAP signaling by rapamycin, resulting in G(1) cell cycle arrest. Rapamycin is used as an immunosuppressant for kidney transplants and is currently under investigation as an antiproliferative agent in tumors because of its ability to block FRAP activity. Although the role of FRAP has been extensively studied in vitro, characterization of mammalian FRAP function in vivo has been limited to the immune system and tumor models. Here we report the identification of a loss-of-function mutation in the mouse FRAP gene, which illustrates a requirement for FRAP activity in embryonic development. Our studies also determined that rapamycin treatment of the early embryo results in a phenotype indistinguishable from the FRAP mutant, demonstrating that rapamycin has teratogenic activity.
Insights
A mutation in the FKBP-12-rapamycin associated protein (FRAP) gene highlights its essential role in embryonic development. Early embryo exposure to rapamycin causes developmental issues similar to the FRAP mutation, indicating teratogenic effects.
Area of Science:
- Molecular Biology
- Developmental Biology
- Biochemistry
Background:
- FKBP-12-rapamycin associated protein (FRAP), also known as mTOR, is a serine/threonine kinase involved in cell growth and proliferation.
- FRAP signaling regulates mRNA translation via p70s6k and 4E-BP1, and its inhibition by rapamycin causes cell cycle arrest.
- Rapamycin is an immunosuppressant and an investigational anti-cancer agent, but its in vivo function, particularly in embryonic development, is not fully understood.
Purpose of the Study:
- To investigate the in vivo function of FRAP during mammalian embryonic development.
- To determine if rapamycin exhibits teratogenic activity by examining its effects on early embryonic development.
Main Methods:
- Identification and characterization of a loss-of-function mutation in the mouse FRAP gene.
- Treatment of early mouse embryos with rapamycin.
- Phenotypic analysis of FRAP mutant and rapamycin-treated embryos.
Main Results:
- A loss-of-function mutation in the mouse FRAP gene demonstrates FRAP's requirement for embryonic development.
- Rapamycin treatment of early embryos produced a phenotype identical to that of the FRAP mutant.
- These findings indicate that rapamycin possesses teratogenic properties.
Conclusions:
- FRAP kinase activity is essential for normal mammalian embryonic development.
- Rapamycin treatment during early embryogenesis results in developmental abnormalities, highlighting its teratogenic potential.