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Prof. Dr. Gerald Thiel

Medizinische Biochemie/Molekularbiologie der Universität des Saarlandes

Regulation of Gene Expression and Signal Transduction Pathways in the Nervous System The laboratory studies gene transcription and signal transduction pathways mainly in cells of the nervous system. The research in the laboratory is focused on the biochemistry and molecular biology of two types of transcriptional regulators, zinc finger proteins (REST, Egr-1) and basic region/leucine zipper proteins (CREB, CREB2, c-jun, c-fos, ATF2, ATF4). In addition, we are interested in those protein kinases regulating transcription. The ongoing research projects in the lab address the roles of transcription factors in the regulation of neuronal genes, in controlling neuronal differentiation, proliferation and programmed cell death. 1. Regulation of neuronal genes The regulatory mechanisms underlying neuron-specific gene transcription are investigated in the lab. A main area of research involves biological functions of the zinc finger protein REST, a transcriptional repressor that silences neuronal genes in nonneuronal cells. Potential target genes of REST are the genes encoding synapsin I, choline acetyltransferase, brain-derived neurotrophic factor, glutamate receptors and others. The regulation of transcription by extracellular signaling molecules (stimulus- transcription coupling) such as neurotransmitters, hormones, growth- and differentiation factors is investigated in the lab with a focus on the biological role of basic-region leucine zipper transcription factors such as CREB, CREB2, ATF2, c-fos and c-jun. As model genes showing stimulus-activated transcription in neuronal cells, we chose the secretogranin II and tyrosine hydroxylase gene. Secretogranin II is an acidic secretory protein found in secretory granules of most peptidergic endocrine cells and neurons. The expression of the secretogranin II gene was shown by us to be controlled by the cAMP-dependent protein kinase. Tyrosine hydroxylase catalyzes the rate-limiting step in the synthesis of catecholamine neurotransmitters. The tyrosine hydroxylase gene was shown to be controlled by basic region/leucine zipper transcription factors including CREB and c-fos. 2. Regulation of proliferation and programmed cell death in neurons and glia cells The transformation of glia to glioma cells require an alteration of the genetic program of the cells. We are in particular interested in studying the role of the zinc finger transcription factor Egr-1 in transformed and non-transformed glia/glioma cells in controling cell proliferation. A variety of environmental signals including growth and differentiation factors, hormones, and neurotransmitters induce Egr-1 gene transcription, thus coupling extracellular signals to long-term responses by altering gene expression. Recently, we have shown that epidermal growth factor and platelet-derived growth factor, potent mitogens for many cell types, induce Egr-1 gene transcription and Egr-1 synthesis in human glioma cells suggesting that Egr-1 connects mitogenic signals with alterations in gene transcription. Apoptosis is a biological process that plays a crucial role in nervous system development and injury. During development, cell death is essential for the regulation of neuronal cell number as well as protection against the further propagation of aberrant cells. In the mature nervous system, inappropriate cell death is implicated as an underlying defect in many types of neurodegeneration as well as acute neurological insults. Understanding the molecular events triggering apoptosis, therefore, is an important step towards the development of effective treatment strategies for such neurological diseases. Furthermore, understanding the apoptotic signaling cascade in tumor cells would help to develop potent anti-tumor drugs that may drive tumor cells into suicide. The lab is interested to elucidate the apoptotic signaling cascades in neurons, neuronal cell lines and glioma cells. In a variety of cell types transcription has been shown to be required for the induction of apoptosis, suggesting that a specific program of gene expression must be executed for apoptosis to occur. We are studying the role of the transcription factors c-fos, c-jun, NFkB, p53 and Egr-1 as integral and necessary parts of apoptotic signaling cascades in these cells. Moreover, the pro-apoptotic or anti-apoptotic role of protein kinases known to activate these transcription factors, are under investigation.

Details


Adresse:
Prof. Dr. Gerald Thiel
Medizinische Biochemie/Molekularbiologie der Universität des Saarlandes
Gebäude 44, Campus der Universität des Saarlandes (UdS)
66421 Homburg
Deutschland
Arbeitsgebiet:
Forschung & Entwicklung
Forschung & Lehre
Expansion:
international
Mitarbeiteranzahl:
1-10
Gründungsjahr:
1997