The role of key regulators of the hypoxia response pathway and collagen synthesis in the regulation of cell polarity

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Faculty of Biochemistry and Molecular Medicine, Lecture hall F101 room, Zoom link https://oulu.zoom.us/j/66189611382?pwd=bnNTL2tvTzFkSXZUVUYxWXYwb1hGdz09

Topic of the dissertation

The role of key regulators of the hypoxia response pathway and collagen synthesis in the regulation of cell polarity

Doctoral candidate

M.Sc. Fazeh Moafi

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Biochemistry and Molecular Medicine

Subject of study

Biochemistry and Molecular Medicine

Opponent

PhD David Bryant, University of Glasgow

Custos

Professor Johanna Myllyharju, University of Oulu

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The role of key regulators of the hypoxia response pathway and collagen synthesis in the regulation of cell polarity

In this thesis we have studied the role of key regulators of hypoxia response pathway and collagen synthesis in the regulation of epithelial cell polarity. Human solid tumours develop poorly oxygenated areas known as hypoxic areas due to uncontrolled proliferation of cells and aberrant formation of blood vessels leading to insufficient transport of oxygen and nutrients.

Cell polarity refers to the asymmetrical distribution of biomolecules or cellular structures between two sides of the cell. Loss of cell polarity is a hall mark of cancer. Furthermore, tumour hypoxia is associated with loss of polarity, but the underlying molecular mechanisms are largely unknown. The key molecular mechanism by which cells sense oxygen tension is through the hypoxia-inducible transcription factors (HIFs).

The current study shows that hypoxia induces a loss of polarity in 3D culture of canine kidney (MDCK) epithelial cells in a HIF1α-dependent manner. We identified the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) as a novel HIF-regulated gene, whose depletion restores cell polarity in hypoxia. HIF prolyl 4-hydroxylases (HIF-P4Hs 1-3) regulate the oxygen-dependent turnover of HIFs.

Our studies revealed that HIF-P4H-1 has a dual role in regulating epithelial cell polarity depending on the cell type and physiological context. Our data demonstrate that knockdown of HIF-P4H-1 may either inhibit cell polarization in normoxia as was the case in the non-malignant MDCK cysts or promote cell polarization as in the malignant colorectal cancer Caco-2 cells. The dual context-dependent role of HIF-P4H-1 in regulating cell polarity should be further studied, as it could potentially uncover novel mechanisms in loss-of-polarity and gain-of-polarity.

Collagens are the most abundant proteins in human body and they give support and integrity for all organs and tissues. Extensive post-translational modifications during collagen synthesis are required for proper assembly and function of collagens, including hydroxylations carried out by collagen prolyl 4-hydroxylases (C-P4Hs), prolyl 3-hydroxylases (P3Hs), and lysyl hydroxylases (LHs). In this thesis, the roles of collagen IV and the collagen hydroxylases in basement membrane formation required for polarization of epithelial cells were studied using 3D culture of MDCK cells. We show that collagen IV and key hydroxylases involved in collagen synthesis have an important role in polarization of epithelial cells.
Last updated: 4.12.2020