NELSON

Functional dissection of the RANTES promoter: Insights into mechanisms of tissue specific regulation of transcription

Peter J. Nelson, Sabine Böhlk, Sabine Fessele and Thomas Werner

Medizinische Poliklinik, LMU Munich, Germany,
Institute of Mammalian Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany and
Genomatix Software GmbH, Munich, Germany

The chemokine RANTES is produced by a variety of cell types in response to diverse stimuli.  The molecular mechanisms involved in transcriptional control of RANTES can vary significantly between the various cells that express the gene and the specific activating stimuli used.  For example, T cells strongly induce RANTES "late" (i.e. 3 to 7 days) after activation through their T cell receptor.  Monocytes do not upregulate RANTES in response to TNF-alpha, IL-1beta or gamma-IFN, but quickly and transiently induce RANTES following stimulation with lipopolysaccaride (LPS) (maximal expression by 6 to 9 hours.  By contrast, fibroblasts and astrocytes produce RANTES in response to TNF-alpha, IL-1 beta and gamma-IFN with the initial expression seen by 6 hours and maximal expression by 48 hours.  The promoter region that regulates these diverse modes of expression may act as an enhancesome.  It is compact, highly conserved over evolution, and can be efficiently studied using computer models of transcriptional control as well as by conventional methods for functional promoter analysis.  The results of an analysis of transcriptional regulation of RANTES in T cells and monocytes will be discussed.