Key enzymes in the synthesis of collagens and the response of cells to hypoxia
Collagen prolyl 4-hydroxylases (C-P4Hs), lysyl hydroxylases (LHs) and lysyl oxidases (LOs) have essential roles in collagen synthesis. A further P4H family (HIF-P4Hs) and an asparaginyl hydroxylase (FIH) regulate the stability and activity of the hypoxia-inducible transcription factors (HIFs), αβ dimers, that play a central role in oxygen homeostasis. To understand the functions of these enzymes, their roles in development and various pathological conditions, and their potential as therapeutic targets, we are utilizing a wide repertoire of methods ranging from analysis of the catalytic and inhibitory properties of the recombinant enzymes to cell biology and animal models. Interestingly, the key enzymes of collagen synthesis are HIF targets and thus regulation of extracellular matrix homeostasis and the hypoxia response are closely linked. Detailed information on the key regulatory enzymes of the hypoxia response will have a major impact in furthering our understanding of how cells and tissues survive and respond to situations of acute or chronic hypoxia. Such information will create novel opportunities for pharmacological intervention in pathological conditions characterized by insufficient oxygen levels such as anemia and ischemia. We are collaborating with FibroGen Inc. in this aspect. Our project belongs to Biocenter Oulu (http://www.oulu.fi/biocenter/groups/myllyharju) and the Academy of Finland Center of Excellence in Cell-Extracellular Matrix Research (http://www.oulu.fi/cecer/). Please refer to these web pages for further information of the project.
Last updated: 14.5.2020