Prof. Dr. Lienhard Schmitz

 JLU Giessen, Department of Biochemistry, Faculty of Medicine


Regulation of the hypoxic gene response by the ubiquitin E3 ligase SIAH2


A significant part of signal-induced protein degradation is mediated by ubiquitin/proteasome-dependent proteolysis. This is exemplified by the transcription factor hypoxia-inducible factor 1a (HIF-1a). HIF-1a is hydroxylated by prolyl hydroxylases under normoxic conditions, thus creating a docking site for the von Hippel-Lindau ubiquitin E3 ligase, which in turn leads to polyubiquitination and proteolytic degradation of HIF-1a. Another interesting regulator of the hypoxic response is the ubiquitin E3 ligase seven-in-absentia 2 (SIAH2), which is inducibly expressed in resonse to hypoxic conditions.                                                                                                                             In this project we want to achieve two major goals: The first goal is to gain a more fundamental understanding of the molecular mechanisms underlying SIAH2-dependent regulation of HIF-1a and of the hypoxic response. This approach requires the generation of tools which allow the manipulation of SIAH2 expression and function by various gain-of-function and also loss-of-function approaches. Doxocyclin- and Auxin-regulated systems are used to control the amount and activity of SIAH2, thus allowing the identification of SIAH2-regulated steps. The second goal is to investigate the function of SIAH2 in the pathophysiological process of maladaptive hypertrophy of the right ventricle of the heart. This work will use Siah2-deficient mice to determine SIAH2-dependent changes in right ventricular architecture and function. Heart-specific SIAH2-interacting proteins and (patho)physiological signaling signatures will be identified.