On the role of the peroxisome in cell differentiation and carcinogenesis

This article reviews the currently available data on the role of peroxisomal function in relation to the processes of cell differentiation and carcinogenesis. In regard to tumourigenesis, both genotoxic and non-genotoxic processes have been considered, and the peroxisomal relationships with these phenomena and with differentiation are described at the level of organelle characteristics, enzyme contents, and the involvement of retinoids, steroid hormones, oxygen free radicals, growth factors, apoptosis, omega-3 polyunsaturated fatty acids and the cellular signalling networks. Overall these data serve to illustrate the unique and distinctive role of the peroxisome in differentiation and carcinogenesis, and point to the advantages of considering the peroxisomal involvement in the holistic context of the differentiation dedifferentiation continuum rather than the narrower focus of non-genotoxic carcinogenesis. The review also outlines the potential for medical benefit arising from a fuller understanding of these peroxisomal affiliations.     

Introduction to Diversity and Speciation in the Prosimii

International Journal of Primatology -     

The synthesis and spectroscopic analysis of the neurotoxic prion peptide 106-126: Comparative use of manual Boc and Fmoc chemistry

Summary A peptide corresponding to residues 106–126 of the human prion protein (PrP) possesses the neurotoxic and amyloidogenic properties of the infectious form of the parental protein. This peptide is now identified as a ‘difficult sequence’ and synthesis using conventional manual Fmoc chemistry was unsuccessful with acylation terminating at a central core of hydrophobic amino acids. The use of tetramethylfluoroformamidinium hexafluorophosphate and 1-methyl-2-pyrrolidone as anti-aggregatory agents in the coupling steps improved the synthesis but still resulted in an incomplete peptide. The incorporation ofN-(2-hydroxy-4-methoxybenzyl)protection at glycine residues 119 and 124 enabled synthesis of the full length peptide in low yield. Synthesis using Boc chemistry within situ neutralisation gave the full length peptide in high yield.     

Association of functional variants of PTPN22 and tp53 in psoriatic arthritis: a case-control study

Recent studies have implicated PTPN22 and tp53 in susceptibility to several autoimmune diseases, including rheumatoid arthritis, suggesting that these genes are important in maintaining immune homeostasis. Because autoimmune diseases may share similar susceptibility loci, investigation of these genes in psoriatic arthritis (PsA) is of potential relevance. As a result we investigated known coding polymorphisms in PTPN22 and tp53 in a homogenous Caucasian PsA cohort from Newfoundland, Canada and an admixed Caucasian PsA cohort from Toronto, Canada. We observed a moderate association of the R620W variant of PTPN22 with PsA in the Toronto population only. Because of the conflicting findings reported regarding the association of PTPN22 with PsA, further studies in other PsA populations are warranted.     

The effect of clofibrate on the phospholipid composition of the peroxisomal membranes in mouse liver

Membranes were prepared from peroxisomes which had been isolated from the livers of normal mice and from mice treated with clofibrate (a hypolipidemic drug and peroxisome proliferator). Phospholipid analysis of these membranes revealed that clofibrate treatment resulted in a decrease in the membrane content of phosphatidylcholine, the most abundant phospholipid, and a concomitant increase in the amount of lysophosphatidylcholine, this latter component reaching a level of almost 6% of the total membrane phospholipid. The concentrations of other phospholipids in these membranes were not significantly altered. The parallel analysis of microsomal membranes demonstrated an analogous increase in the level of lysophosphatidylcholine following clofibrate treatment. In control experiments with microsomal membranes employing quinacrine, an inhibitor of phospholipase A2, the increased lysophosphatidylcholine concentration was still observed in clofibrate-treated animals. As well, a decrease in the proportion of microsomal phosphatidylcholine with clofibrate treatment was seen when quinacrine was used. Fatty acid analysis of the phosphatidylcholines from peroxisomal membranes showed some minor changes, including an increase in one component tentatively identified as docosahexaenoic acid, in clofibrate-treated animals. Overall, these data demonstrate that clofibrate causes a marked perturbation of the phospholipid composition of peroxisomal membranes, and are interpreted as indicating that the main site of action of the drug is the deacylation-reacylation cycle between phosphatidylcholine and lysophosphatidylcholine.     

Sequential alterations in the micro-localization of catalase in mouse liver after treatment with hypolipidemic drugs

Summary A comparative study has been carried out on the micro-localization of catalase in mouse tissues subsequent to treatment with a representative range of hypolipidemic drugs.A commonality of effect was shown by clofibrate (ethyl--p-chlorophenoxyisobutyrate), Wy-14,643 (4-chloro-6-[2,3 xylidino)-2-pyrimidinylthio] acetic acid), RMI-15,414 (5-tetradecyloxy-2-furancarboxylic acid) and aspirin (acetyl salicylic acid), in that treatments with each of these drugs was associated with the release of peroxisomal catalase into the cytoplasmic compartment of liver and kidney. It was also noticeable that this increased cytosolic activity was characterized by the presence of an aged form of the enzyme with different mobility and activity characteristics to that of the peroxisomal enzyme.Possible molecular bases for these effects and their relationship to peroxisomal biogenesis are discussed.