Rapamycin, mammalian target of

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Rapamycin is an immunosuppressive diug and an inhibitor of S6K1 (also known as p70S6-kinase) which phosphorylates ribosomal S6 protein. S6K1 is activated in response to insulin via activation of Akt. Rapamycin binds to a specific target protein (mTOR, mammalian target of rapamycin) which is functionally located downstream of Akt, but upstream... 

Insulin and other growth factors result in the phosphorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insuhn causes a marked posttranscriptional... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Brunn, G.J., Williams, J., Sabers, C., Weiderrecht, G., Lawrence, J. C., and Abraham, R. T. (1996). Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBOJ. 15, 5256-5267. 

Manning, B. D., and Cantley, L. C. (2003). United at last The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signaling. Biochem. Soc. Trans. 31, 573-578. 

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

Del Bufalo D, Ciuffreda L, TriscinogUo D, Desideri M, Cognetti F, Zupi G Milella M. (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirohmus. Cancer Res 66 5549-5554. 

Mita MM, Mita AC, Chu QS, Rowinsky EK, Eetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. (2008) Phase Itrial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573 MK-8669)... 

Chan S. Targeting the mammalian target of rapamycin (mTOR) a new approach to treating cancer. Br J Cancer 2004 91(8) 1420-4. 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

Binds to an immunophilin protein to form a complex which inhibits the activation ot the mammalian Target of Rapamycin (mTOR)ulatory kinase. This inhibits T lymphocyte activation and proliferation by IL-2. IL-4, and IL-5. 

Sirolimus binds to the cytosolic protein FK-binding protein R (FKBP-12) but does not block calcineurin activity. It does not bind to cyclophilins, which are cytosolic receptors for cyclosporine. Unlike cyclosporine and tacrolimus, sirolimus does not inhibit the activation of NFAT responsive genes. After binding to its cytosolic receptors, sirolimus inhibits a protein kinase, the mammalian target of rapamycin (mTOR) pathway, via suppression of PP2-A. When mTOR is inhibited, the cells will not proceed to the S phase, and the cell cycle will be blocked (Fig. 4.3). As a result, sirolimus blocks T-cell proliferation but its effects are downstream of the IL-2 receptors. IL-2 binding to its receptors activates intracellular protein kinases that in turn activate gene transcription and T-cell proliferation. 

Mechanism of Action. Unlike other immunosuppressants (cyclosporine, tacrolimus), sirolimus does not interfere directly with cytokine production. Instead, sirolimus inhibits the function of a specific enzyme commonly known as the mammalian target of rapamycin (mTOR).37,42 This enzyme plays a key role in signaling pathways that promote the growth and proliferation of T and B cells.37,45 By inhibiting this enzyme, sirolimus causes cell division to stop at a specific stage (Gl), thereby limiting the ability of these cells to mount an attack on transplanted tissues.65... 

Sirolimus Inhibits mammalian target of rapamycin and cell cycle progression Porcine coronary artery Drug-eluting stent Significant reduction in neointimal hyperplasia (106)... 

Sirolimus, a macrolide antibiotic, in one mode of action, binds to FK506-binding protein (FKBP12), inhibiting the activation of mammalian target of rapamycin (mTOR), which, in turn, blocks the cellular transition from G, to the S phase of the cell cycle (35). Sirolimus was approved by the Food and Drug Administration (FDA) in 1999 for the prevention of renal... 

Bolster, D. R., Crozier, S. J., Kimball, S. R., and Jefferson, L. S. 2002. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 277 23977-23980. 

Sirolimus (rapamycin) is another macrolide, produced by Streptomyces hydroscopi-cus. Its immunosuppressant action, evidently, does not appear to involve inhibition of calcineurin. It forms a complex with the FK protein, imparting a special conformation on it and the complex then inhibits the mTOR (mammalian target of rapamycin) phosphatase. The latter operates in the signaling path leading from the interleukin-2 receptor to activation of mitosis in lymphocytes. Thus, sirolimus inhibits lymphocyte proliferation. It is approved for the prevention of transplant rejection. 

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