C 3-Professur für Physiologie (Gekle)
Röntgenring 9, 97070 Würzburg
Other participating persons and organisations:
Research foci (and basic equipment-based research projects):
The corticoid hormones aldosterone and cortisone play an important role in the regulation of cell metabolism, cell growth, volume homeostasis, blood pressure as well as during pathological tissue modifications, like in heart or kidney. Corticoids unfold their action, at least in part, after binding to the cytosolic receptors GR and MR by modulating the expression of proteins, many of which have not yet been identified. The EGF-EGFR complex triggers a network of signalling pathways, culminating in responses like cell proliferation, migration, epithelial transport and cancer. During the last years it has been shown that steroid hormones, including corticoids, interact with the EGFR signalling pathways, either in a stimulatory or inhibitory way. In many studies a rapid modulatory action, taking place at the EGFR in the cell membrane, has been described. However, there are also reports showing that steroids may influence the expression of EGFR-ligands or the EGFR itself. Since enhanced expression of EGFR promotes carcino-genesis, knowledge regarding the interaction of corticoid receptors with EGFR function or ex-pression yields information about mechanisms of carcinogenesis as well as about novel strate-gies in cancer therapy. Departing from our previous work and data in literature we want to in-vestigate the mechanisms and consequences of human MR- and human GR-induced EGFR expression. For this purpose we will start with heterologous expression systems to determine (a) the effect of hMR/hGR-expression on EGFR-expression, (b) the role of corticoid hormones and their antagonists in this process, (c) the signalling mechanisms involved and (d) the EGF-responsiveness with respect to cellular signalling and cell proliferation. Subsequently, the stud-ies will be extended to more differentiated cells lines and finally to primary human cells from lung, kidney, mammary gland and prostate.
GEKLE, M., R. FREUDINGER, S. MILDENBERGER AND C. SAUVANT. Determination of basolateral Na+/H+-exchange activity in MDCK-cells using a multiwell-multilabel-reader. Anal. Biochem. 269:174-178, 2001.
GEKLE, M., R. FREUDINGER, S. MILDENBERGER, K. SCHENCK, I. MARSCHITZ AND H. SCHRAMEK. Rapid activation of Na+/H+-exchange in MDCK-cells by aldosterone involves MAP-kinases ERK 1/2. Eur. J. Physiol. (Pflügers Arch.) 441:781-786, 2001.
ORLOV, S.N., N.O. DULIN, F. GAGNON, M. GEKLE, J.G. DOUGLAS, J. TREMBLAY, J.H. SCHWARTZ AND P. HAMET. Purinergic modulation of Na+,K+,Cl- cotransport and MAP kinases in collecting ducts is limited to intercalated cells. J. Memb. Biol. 172:225-234, 1999.
GEKLE, M., R. FREUDINGER, S. MILDENBERGER AND S. SILBERNAGL. Rapid actions of aldosterone on cells from renal epithelium: The role of EGF-receptor signaling. Steroids 67:499-504, 2002.
GEKLE, M., R. FREUDINGER, S. MILDENBERGER AND S. SILBERNAGL. Aldosterone interaction with epidermal growth factor receptor signalling in MDCK cells. Am. J. Physiol. 282:F669-679, 2002.
BOURCIER, N., R. GRYGORCZYK, M. GEKLE, Y. BERTHIAUME, AND S. N. ORLOV. Purinergic-induced ion current in monolayers of C7-MDCK cells: role of basolateral and apical ion transporters. J.Membr.Biol. 186: 131-143, 2002.
KRUG, A., C. SCHUSTER, B. GASSNER, R. FREUDINGER, S. MILDENBERGER, J. TROPPMAIR AND M. GEKLE. Human EGF receptor 1 (HER1) expression renders CHO cells sensitive to alternative aldosterone signaling. J. Biol. Chem. 2002 (in press).