Inhibitors of gene expression

Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, Kawasaki AM, Cook PD, Freier SM (1993) Evaluation of 2 -modified oligonucleotides containing 2 -deoxy gaps as antisense inhibitors of gene expression, J Biol Chem 268 14514-14522... 

Sopchik AE, Jiao X-Y, Bentrude WG (1999) Phosphorus, Sulfur and Silicon 144-146 373 Cohen JS (ed) (1989) Oligonucleotides, antisense inhibitors of gene expression. CRC, Boca Raton FI... 

Caruthers, M. H., Synthesis of oligonucleotides and oligonucleotide analogues, in Oligodeoxynucleotides — Antisense Inhibitors of Gene Expression, Cohen, J. S., Ed., CRC Press, Boca Raton, FL, 1989, 7. 

Miller, P.S. and Ts o, P O P. (1988) Oligonucleotide inhibitors of gene expression in living cells new opportunities in drug design. Ann. Reports Med. Chem., 23, 295-304. 

Nechers, L.M. (1989) Antisense oligonucleotides as a tool for studying cell regulation mechanism of uptake and application to the study of oncogene function. In J.S.Cohen (ed.) Oligodeoxyribonucleotides Antisense Inhibitors of Gene Expression. Macmillan Press, London. 

Cohen, J.S. (1989) Oligodeoxynucleotides antisense inhibitors of gene expression. In S.Neidle and W.Fuller (eds) Topics in Molecular and Structural Biology. The MacMillan Press, London, 12, 255. 

Stein CA, Tokinson JL, Yakubov L, Phosphorothioate oligodeoxynucleotides antisense inhibitors of gene expression Pharmacol Ther 1991 52 365-384,... 

GoodchildJ. Inhibition of gene expression by oligonucleotides. In Cohen J, ed. Oligonucleotides Antisense Inhibitors of Gene Expression, London, UK MacMillan press, 1989 53-77. 

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Thuong, N T, Asseline, U, Montenay-Garestier, T, in Oligodeoxynucleotides, Antisense Inhibitors of Gene Expression, Cohen, J S, Editor. 1989, Macmillan London, p. 25-51. 

In order to study the integration of secondary product formation into sporulation, different methods have been used. By the use of whole cell- and cell free-systems it has been demonstrated that the production of secondary metabolites occurs at different stages in growth. Furthermore, experiments with mutants and inhibitors of gene expression indicate that the formation of some secondary products, among which are sulpholactic acid, dipicolinic acid, brown pigments and peptide antibiotics, is closely linked to the sporulation process (Ref. 14, 19). 

Transition from the trophophase to the idiophase of hy-phal cells is not stopped by inhibitors of MA synthesis (13). It is, however, prevented by inhibitors of gene expression (a. above) indicating that it depends on differential gene expression in already existing cells. These results show that the specialization of hyphal cells is a multistep process which with respect to the expression of alkaloid biosynthesis in emerged cultures includes at least four stages ... 

L, Hover and M. Luckner, Influence of inhibitors of gene expression on processes of cell specialization during the idiophase development of Penicillium cyclopium WESTIING, Biochem, Physiol. Pflanzen 168, 79 - 85 (197 5TI... 

B Measurement of the influence of inhibitors of gene expression on the formation of secondary products or on the formation of enzymes involved in secondary metabolism. 

Enzymes of alkaloid biosynthesis are induced in a coordinated manner by an internal signal during development of the mold. However, the rates of alkaloid production increase later than enzyme activities, The increase of both processes can be stopped by addition of inhibitors of gene expression, e.g., 6-fluorouracil or cycloheximide (cf. arrows), indicating that alkaloid production is controlled by the formation of a protein which is not an enzyme of alkaloid biosynthesis. Ordinate relative values A A anthranilic acid adenylyl transferase (a) CD cyclopeptine dehydrogenase (v) DE dehydrocyclopeptine epoxidase ( ) CmH cyclopenin m-hydroxvlase (A)... 

In some cases, however, the regulation of the in vivo activity of secondary metabolic enzymes is more complicated. In the hyphae of Penicillium cyclopium the activities of the enzymes of benzodiazepine alkaloid biosynthesis (D 8.4.2) are measurable at a relatively early stage of the mold s development, whereas alkaloid formation is expressed later (Fig. 8). The increase of the rate of biosynthesis is immediately stopped by inhibitors of gene expression, e.g., 5-fluorouracil or cycloheximide (D 3.3.7), even at developmental stages at which the in vitro measurable enzyme activities have already their maximum levels. This indicates the existence of a protein limiting the rate of alkaloid formation, which is synthesized much later than the investigated enzymes. 

For most of the different dephospho oligonucleotide analogs, no extensive investigations were reported so that no detailed practical procedures can be given in this chapter. The main scope of this chapter IS therefore to show which types of dephospho oligonucleotides have been synthesized so far, what their chemical properties are, and whether their physical characteristics provide a basis to design new inhibitors of gene expression of potential therapeutic value. 

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