Regulatory mechanisms at the apex of the hypoxic response in lung vascular remodeling

• Applicant: Professor Dr. M. Lienhard Schmitz
• Subject Area: Anatomy and Physiology ; Cardiology, Angiology
• Term: from 2009 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 160650752

• Final Report Year: 2013

Final Report Abstract

Hypoxia-induced proliferation of cells can lead to PH, but the molecular mechanisms are not well understood. Based on the identification of the kinase HIPK2 and the ubiquitin E3 ligase SIAH2 as important regulators of the hypoxic response we have investigated their function in and regulation in hypoxia. We identified the DNA sequence elements leading to chromatin attachment and gene repression by HIPK2. Regulation of the kinase by a scaffold protein was found and a hypoxia/redox-dependent modification of HIPK2 by acetylation. New SIAH2 phosphorylation sites were found and characterized. A contribution and the (patho)physiological role of SIAH2 in lung diseases was revealed from patient material and in mouse models. press release: http://www.uni-giessen.de/cms/ueber-uns/pressestelle/pm/pm%2097-12/

Publications

• (2010) The WD40 repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. EMBO J. 29, 3747-3749
  Ritterhoff, S., Farah, C.M., Grabitzki, J., Lochnit, G., Skurat, A.V. and M.L. Schmitz
  
• (2012) A redoxregulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress. Mol Cell. 2012 May 25;46(4):472-83
  de la Vega L, Grishina I, Moreno R, Krüger M, Braun T and M.L. Schmitz
  (See online at https://doi.org/10.1016/j.molcel.2012.03.003)
• (2012) Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J. Mol. Cell Biol. 4, 316-330
  Pérez, M., García-Limones, C., Zapico, I., Marina, A., Schmitz, M.L., Muñoz, E. and M.A. Calzado
  (See online at https://doi.org/10.1093/jmcb/mjs047)
• (2012) Regulation of the tumor suppressor PML by sequential posttranslational modifications. Front. Oncol. 2:204
  Schmitz, M.L. and I. Grishina
  (See online at https://doi.org/10.3389/fonc.2012.00204)
• (2012) SIAH-mediated ubiquitination and degradation of acetyl-transferases regulates the p53 response and protein acetylation. Biochim. Biophys. Acta 1823, 2287-2296
  Grishina, I., Debus, K., García-Limones, C., Schneider, C., Shresta, A., García, C., Calzado, M.A. and M.L. Schmitz
  (See online at https://doi.org/10.1016/j.bbamcr.2012.09.011)