Olaf Heidenreich

Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells.

HTLV-1 infection causes an adult T cell leukemia in humans. The viral encoded protein tax, is thought to play an important role in oncogenesis. Our previous data obtained from a tax transgenic mouse model revealed that tax transforms mouse fibroblasts but not thymocytes, despite comparable levels of tax expression in both tissues. Constitutive tyrosine phosphorylation of a 130-kD protein(s) was observed in the tax transformed fibroblast B line and in HTLV-1 transformed human lymphoid lines, but not in thymocytes from Thy-tax transgenic mice. Phosphotyrosine immunoprecipitation followed by Western blot analysis with a set of Jak kinase specific antibodies, identified p130 as Jak2 in the tax transformed mouse fibroblastic cell line and Jak3 in HTLV-1 transformed human T cell lines. Phosphorylation of Jak2 in tax transformed cells resulted from high expression of IL-6. Tyrosine phosphorylation of this protein could also be induced in Balb/c3T3 cells using a supernatant from the B line, which was associated with induction of cell proliferation. Both phosphorylation and proliferation were inhibited by IL-6 neutralizing antibodies. Constitutive phosphorylation of Jak kinases may facilitate tumor growth in both HTLV-1 infected human T cells and the transgenic mouse model.

Application of antisense technology to therapeutics

Antisense oligonucleotides inhibit gene expression by binding in a sequence-specific manner to an RNA target. Modern nucleotide chemistry has enabled the synthesis of chemically modified oligonucleotides that are highly resistant to nuclease degradation. Among other applications, these agents are currently being evaluated as potential antiviral and anticancer drugs. However, several unsolved problems remain. Poor efficiency of delivery to cells, tissue toxicity and antisense-independent biological effects of oligonucleotides currently limit the widespread application of antisense oligonucleotides to human disease. This article reviews some of the applications of antisense oligonucleotides and discusses problems associated with these applications.

Ribozyme in der molekularen Medizin

Ribozyme sind RNA-Molekule mit enzymatischer Aktivitat, die Anfang der 80er Jahre durch die Untersuchung von RNA-Prozessierung entdeckt wurden. Mehrere unterschiedliche RNAs, wie bestimmte Introns, die RNA-Untereinheit der RNase P oder die selbstspaltenden RNAs von Pflanzenviroiden, sind bisher in der Literatur beschrieben worden. Die bis jetzt beschriebenen Aktivitaten von Ribozymen umfassen im wesentlichen die Spaltung und Ligierung von RNA-Molekulen. Insbesondere aufgrund ihrer Fahigkeit, RNA sequenzspezifisch zu spalten, wurden Ribozyme schon bald zur Regulation der Genexpression in Zellkulturen eingesetzt. Mittlererweile stehen bereits transgene Tiere, die Ribozyme exprimieren, zur Verfugung, und Ansatze, die HIV-Infektion mit Ribozymen zu behandeln, stehen an der Schwelle zu klinischen Studien. Ribozyme konnen in der Zelle von vorher eingebrachten DNA-Sequenzen endogen transkribiert werden oder aber, wie Antisenseoligonukleotide, Zellen von ausen (exogen) zugefuhrt werden. Wahrend der 1. Fall ein gentherapeutischer Ansatz ist, wird im 2. Fall eine Droge verabreicht.