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A mammalian protein targeted by G1-arresting rapamycin-receptor complex
E J Brown1, M W Albers, T B Shin
1Department of Chemistry, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138.
Nature
|June 30, 1994
Summary
Rapamycin and FK506 bind FKBP12 but affect different cell pathways. Researchers identified a mammalian FKBP-rapamycin-associated protein (FRAP) crucial for rapamycin
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Rapamycin and FK506 are natural products binding FKBP12.
- These complexes inhibit distinct signaling pathways, affecting cell cycle progression.
- FKBP12-rapamycin inhibits G1 phase progression and mitogenic signaling pathways.
Purpose of the Study:
- To isolate and characterize a mammalian protein associated with the FKBP-rapamycin complex.
- To investigate the role of this protein in rapamycin's mechanism of action.
- To identify the human homolog of yeast genes linked to rapamycin sensitivity.
Main Methods:
- Isolation of a mammalian FKBP-rapamycin-associated protein (FRAP).
- Correlation of FRAP binding with rapamycin's cell cycle inhibitory effects.
- Peptide sequencing of FRAP to isolate a human cDNA clone.
Main Results:
- A mammalian FRAP was isolated, binding to FKBP-rapamycin complexes.
- FRAP binding correlated with the inhibition of cell-cycle progression by rapamycin analogs.
- A human cDNA clone related to yeast DRR1/TOR1 and DRR2/TOR2 was identified.
Conclusions:
- FRAP is a key component of the FKBP-rapamycin signaling complex in mammals.
- The identified human FRAP homolog is evolutionarily conserved with yeast TOR genes.
- This discovery provides insights into the molecular targets of rapamycin and FK506.