Mechanism of action of the immunosuppressant rapamycin

Dumont, Francis J.; Su, Qingxiang

doi:10.1016/0024-3205(95)02233-3

Cited by 312 publications

(217 citation statements)

References 157 publications

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“…Therefore, G1 cell-cycle arrest in PHA-PBMCs paralleled decreased expression of p21 Waf1 and simultaneous increase of p27 Kip1 observed in Figure 2. Similarly, in N1186 cells, the reduction of p21 Waf1 and induction of p27 Kip1 (Figure 2 Decreased ability of N1186 cells to arrest in G1 following rapamycin treatment correlates in particular with a less evident induction of p27 Kip1 rather than downregulation of p21 Waf1 , consistent with the notion that rapamycin induced G1 cell-cycle arrest is mediated by p27 Kip1 (Dumont et al, 1995).…”

Section: Cell-cycle Regulation In Early and Late Phases Of Htlv-i Infsupporting

confidence: 68%

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

et al. 1999

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Section: Cell-cycle Regulation In Early and Late Phases Of Htlv-i Infsupporting

confidence: 68%

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

et al. 1999

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“…Even though FK506 and rapamycin bind to the same protein, they have different mechanisms of action in cells. FK506 inhibits T cell proliferation by blocking the Ca 2+ /calcineurindependent transcriptional activation of genes required for growth, whereas rapamycin interferes with growthpromoting cytokine signaling [33]. Interleukin-2 (IL-2) induced S6K activation in a T cell line was extremely sensitive to rapamycin inhibition (IC 50 = 0.05 nM) [34].…”

Section: Rapamycin and Rapalogsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

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“…A large number of groups have already shown the ability of rapamycin to diminish pathology in various animal model immune diseases. 9 Interestingly, rapamycin inhibits the chronic/acute organ rejection process that is not suppressed by cyclosporine and FK506. 30,31 It has been suggested that these immunosuppressive effects of rapamycin result from its ability to inhibit proliferation by interfering with the function of mTOR.…”

Section: Biological Activities Of Rapamycin and Its Analogsmentioning

confidence: 99%

“…FK506 inhibits interleukin 2-mediated T-cell proliferation by blocking the Ca 2+ /calcineurindependent transcriptional activation of the genes responsible for growth, whereas rapamycin prevents growth-promoting cytokine signaling by interacting with a mammalian target of rapamycin (mTOR) instead of calcineurin (Figure 2). 9 In the early 1990s, a study on the biosynthesis of immunosuppressant rapamycin was begun by Demain's research group at Massachusetts Institute of Technology. 10 Classical feeding experiments with isotope-labeled precursors provided evidence that rapamycin is formed through a polyketide pathway and its macrolactone ring is derived from acetate, propionate and methionine.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

et al. 2010

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Rapamycin and its analogs are clinically important macrolide compounds produced by Streptomyces hygroscopicus. They exhibit antifungal, immunosuppressive, antitumor, neuroprotective and antiaging activities. The core macrolactone ring of rapamycin is biosynthesized by hybrid type I modular polyketide synthase (PKS)/nonribosomal peptide synthetase systems primed with 4,5-dihydrocyclohex-1-ene-carboxylic acid. The linear polyketide chain is condensed with pipecolate by peptide synthetase, followed by cyclization to form the macrolide ring and modified by a series of post-PKS tailoring steps. The aim of this review was to outline past and recent advances in the biosynthesis and regulation of rapamycin, with an emphasis on the distinguished contributions of Professor Demain to the study of rapamycin. In addition, this article describes the biological activities as well as mechanism of action of rapamycin and its derivatives. Recent attempts to improve the productivity of rapamycin and generate diverse rapamycin analogs through mutasynthesis and mutagenesis are also introduced, along with some future perspectives.

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Mechanism of action of the immunosuppressant rapamycin

Cited by 312 publications

References 157 publications

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

Rapamycin and mTOR kinase inhibitors

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

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