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  • 1
    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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  • 2
    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
    Library Location Call Number Volume/Issue/Year Availability
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