Posttranslational processing of so-called CaaX proteins has received much attention in the past two decades due to the important roles these proteins play in biological regulations and diseases (1, 2). This processing is initiated by isoprenoid modification of the cysteine residue of the C-terminal CAAX motif of the protein, subsequent proteolytic removal of the three C-terminal amino acids, i.e. the ϪAAX residues, and the methylation of the newly exposed carboxyl group of the prenylated cysteine residue. The overall process, termed protein prenylation, has been shown to be important for the localization, stability, and ultimate functions of a broad array of CaaX proteins (3).Most members of the Ras superfamily of GTPases are CaaX proteins, and Ras proteins themselves, which are farnesylated, have been extensively studied due to the high prevalence of dysregulated Ras signaling in human cancers (4). Inhibitors of protein farnesyltransferase (FTase) 2 have been under development as anticancer agents for over a decade, but their efficacy, especially in solid tumors, has been disappointing (5, 6). The realization that some CaaX proteins, including forms of Ras in which mutations are prevalent in human tumors, are subject to alternative prenylation by protein geranylgeranyltransferase I when FTase is inhibited (7) spurred efforts to target the postprenylation processing steps of proteolysis and methylation since each of these steps is catalyzed by a single enzyme that acts on both farnesylated and geranylgeranylated proteins (8, 9). In particular, targeting of CaaX protein methylation via inhibition of the enzyme responsible, isoprenylcysteine carboxylmethyltransferase (Icmt), through both genetic and pharmacological approaches, has been shown to dramatically impair oncogenesis in several tumor cell models (10, 11).The mechanism(s) through which inhibition of Icmt impacts on cell proliferation and oncogenesis are still far from clear. Interference with cell cycle progression, however, is a cornerstone of many chemotherapeutic agents, and both 2 The abbreviations used are: FTase, farnesyltransferase; Icmt, isoprenylcysteine carboxylmethyltransferase; LC3, microtubule-associated protein 1 light chain 3; LC3-II, activated form of LC3; J3, cysmethynil analog 1-octylm-tolyl-1H-indole; atg5, autophagy related 5 homolog; 4EBP1, eukaryotic initiation factor 4E-binding protein 1; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; DMEM, Dulbecco's modified Eagle's medium; 3-MA, 3-methyladenine; siRNA, small interfering RNA; DMSO, dimethyl sulfoxide.

Given that p53 over-expression in primary glioblastomas is predominantly detected in the absence of mutations of the gene, and that both survivin and p53 are regulated at the level of the protein by the same ubiquitin-proteosome degradation pathway, these results suggest that primary glioblastomas may occur as a result of a failure of appropriate protein degradation regulation.

Meningiomas have mesenchymal differentiation and studies have confirmed that meningiomas express intermediate filaments of both mesenchymal and epithelial types including vimentin and keratin. To further characterize their mesenchymal properties, particularly the role of factors requiring adhesion, extracellular matrix degradation, and migration, meningiomas were examined for a panel of extracellular matrix markers. Immunoreactivity to the matrix metalloproteinases, MMP-2 and MMP-9, and their tissue inhibitor, TIMP-1, and to an adhesion factor, galectin-3 were found in the majority of cases. The present study suggests that expression of these factors in benign meningiomas is ubiquitous and unrelated to tumor location. Therefore, these factors of the extracellular matrix may be potential targets of future therapy.

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