Molecular basis for specific regulation of the stress sensor IRE1 in cancer cells

Lead Research Organisation: University of Leeds
Department Name: Inst of Molecular & Cellular Biology

Abstract

The unfolded protein response (UPR) is a key adaptive cellular mechanism to detect and attenuate the accumulation of misfolded proteins inside the endoplasmic reticulum (ER). The UPR is crucial for cancer cell survival and drug resistance. This project aims to explore how IRE1 mutations associated with different cancers alter IRE1 conformation and activity. We are using biophysical and biochemistry assays and state-of-the-art structural biology approaches based on NMR, cryo-EM, and computational modeling to elucidate the molecular origins of IRE1 mutations in human cancers and understand the molecular mechanisms on how these mutations help cancer cells to survive. The project aims at invistigation of the complex IRE1 signaling mechanism as well as development of a new interdisciplinary approach for detailed characterization of multicomponent supramolecular systems.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 30/09/2015 29/09/2023
1646704 Studentship BB/M011151/1 30/09/2015 29/09/2019 Nicholas Hurst
 
Description I have partially developed a method to study an important cellular stress response protein in the laboratory, in a more efficient way than previously available.
I have also been able to investigate how cancer-associated mutations to a domain of the stress response protein perturb its activity and may impact the growth of tumours.
Exploitation Route New information about the cancer-associated mutations of the protein maybe able to aid drug development in cancer, and over all the understanding of how the protein functions.
Sectors Pharmaceuticals and Medical Biotechnology