Der Transkriptionsfaktor FKHR interagiert mit STAT-Faktoren und verstärkt die IL-6-Signaltransduktion

It is well known that on the one hand growth factors are able to induce proliferation but on the other hand reduce the synthesis of acute phase proteins in hepatocytes. This thesis will give a possible reason for this observation. An important pathway of signal transduction of growth factors depends on the activation of PI3 kinase and the ProteinkinaseB (PkB). Within the cell the IL6 signal is mediated via Janus kinases and STAT factors. This results in production and secretion of acute phase proteins in hepatocytes. For the first time it was possible to identify the transcription factor FKHR as a crosslink molecule between the PI3 kinase/PKB signal transduction pathway and the IL6/gp130/Jak/STAT cascade. The synergism of the transcription factors STAT3 and FKHR could be proven and FKHR was able to increase the IL6 induced STAT3 mediated transcription of responsive genes significantly. It was ruled out that a STAT3 independent gene induction at the alpha2-macroglobulin promotor by FKHR is possible. The physical interaction of FKHR and STAT3 was proven. After stimulation with IL6 the colocalisation of the two proteins in the nucleus could be observed by immunofluorescence labelling methods. The interdependency of the foxo-transcription factor FKHR and the STAT factors is specific. Apart from STAT3, a synergistic effect was shown for STAT1 as well but could not be observed for STAT5 or Smad7. Growth factors activate via PI3 kinase the PkB which phosphorylates FKHR at serin/threonin phosphorylation sides. This forces FKHR to leave the nucleus. A reduction of acute phase proteins synthesis and secretion results from stimulating HepG2 cells with insulin, FCS, or growth factors. Confirming the observations the negative effect of insulin or serum containing media on acute phase protein producion is revoked by the PI3 kinase inhibitor wortmannin, as well as it is revoked by the use of mutants of FKHR, which can not be phosphorylated.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2004

Author dc:creator

• Feld, Florian

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/610
• Medizin
• IL6
• gp130
• STAT3
• PI3 Kinase
• FKHR
• apha-2-Makroglobulin
• Akt
• PkB

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-121247%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:59465