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  • 11
    ISSN: 1432-0614
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Chaetomellic acids A and B, isolated from Chaetomella acutiseta, are specific inhibitors of farnesyl-protein transferase that do not inhibit geranylgeranyl transferase type 1 or squalene synthase. Chaetomellic acids A and B are reversible inhibitors, resemble farnesyl diphosphate and probably inhibit FPTase by substituting for farnesyl diphosphate. Chaetomellic acid production appears to be widespread within the genus Chaetomella.
    Type of Medium: Electronic Resource
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  • 12
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 6 (1989), S. 306-315 
    ISSN: 0887-3585
    Keywords: oncogene ; GTP-binding protein ; cancer ; S. cerevisiae adenylyl cyclase ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Biologically active forms of Ras complexed to GTP can bind to the GTP ase-activating protein (GAP), which has been implicated as a possible target of Ras in mammalian cells. In order to study the structural features of Ras required for this interaction, we have evaluated a series of mutant ras proteins for the ability to bind GAP and a series of Ras peptides for the ability to interfere with this interaction. Point mutations in the putative effector region of Ras (residues 32-40) that inhibit biological activity also impair Ras binding to GAP. An apparent exception is the Thr to Ser substitution at residue 35; [Ser-35]Ras binds to GAP as effectively as wild-type Ras even though this mutant is biologically weak in both mammalian and S. cerevisiae cells. In vitro, [Ser-35]Ras can also efficiently stimulate the S. cerevisiae target of Ras adenylyl cyclase, indicating that other factors may influence Ras/protein interactions in vivo. Peptides having Ras residues 17-44 and 17-32 competed with the binding of RAS to E. coli-expressed GAP with IC50 values of 2.4 and 0.9 μM, respectively, whereas Ras peptide 17-26 was without effect up to 400 μM. A related peptide from the yeast GTP-binding protein YPT1 analogous to Ras peptide 17-32 competed with an IC50 value of 19 μM even though the YPT1 protein itself is unable to bind to GAP. These results suggest that determinants within Ras peptide 17-32 may be important for Ras binding to GAP.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 13
    Electronic Resource
    Electronic Resource
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 59 (1995), S. 145-150 
    ISSN: 0730-2312
    Keywords: CAAX peptidomimetic ; farnesyl-protein transferase ; protein prenylation ; ras oncogene ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Protein prenylation, adding either the 15-carbon isoprenoid farnesy1 or the 20-carbon isoprenoid geranylgeranyl to cysteine residue(s) at or near the C-termini of proteins, is a recently identified post-translational modification that localizes some proteins to a membrane compartment. One of the most intensely studied prenylated proteins is Ras, a low molecular weight GTP-binding protein that plays an important role in the regulation of cell proliferation. Proteins encoded by ras genes with oncogenic mutations are capable of tranforming cells in culture. Such mutate ras genes are frequently found in a wide variety of human tumors. Localization of the Ras oncoprotein to the cytoplasmic face of the plasma membrane via farnesylation is essential for efficient cell transforming ability. Thus, inhibition of the Ras farnesylation reaction is a possible anti-cancer strategy.Several strategies have been employed to inhibit Ras farnesylation, including inhibition of isoprenoid biosynthesis and inhibition of the enzyme which catalyzes the farnesylation reaction, farnesyl-protein transferase (FPTase). Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme. A reductase, the rate limiting enzyme in isoprenoid biosynthesis, inhibit Ras farnesylation and block the growth of ras-transformed cells. However, antiproliferative effects do not result from speicific inhibition of Ras farnesylation; they are also observed in cells transformed by raf, which is independent of Ras farensylation. A more specific approach to inhibiting Ras farnesylation is to inhibit FPTase. Using randon screeing of natural products and a rational design approach, a variety of compounds that specifically inhibit FPTase have been isolated. Several of these compounds were found to block the farnesylation of Ras proteins in cell culture and were able to block the anchorage-independent growth of ras-transformed cells and human tumor cell lines. FPTase inhibitors also blocked the morphologic alteration associated with ras-induced transformation of mammalian cells. In contrast, these compounds did not affect the growth or morphology of cells transformed by the raf or mos oncogenes, which do not require farnesylation to achieve biological activity. Furthermore, these compounds suppressed the growth of tumors arising from ras-transformed cells in nude mice in the absence of systemic toxicity. Control tumors formed by raf- or mos- transformed cells were not affected by these compounds. These studies suggest that FPTase inhibitors might be safe and effective chemotherapeutic agents.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 14
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    BioEssays 16 (1994), S. 187-191 
    ISSN: 0265-9247
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Advances in the understanding of Ras oncoprotein function suggest novel points for anti-tumor intervention. First, upstream-acting guanine nucleotide exchange factors and SH2/SH3 domain-containing adaptor proteins that link Ras with growth factor receptor tyrosine kinases have recently been characterized. Second, work on downstream-acting Ras effector functions including the Ras GTPase-activating protein (p120GAP) and the Raf kinase has revealed direct biochemical interactions that are functionally required for oncogenic Ras signalling. We summarize progress in these areas and discuss the potential for novel applications to anti-cancer chemotherapy.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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