About the Project
Mammalian cells that experience ER stress mount a protective response to this stress, called the unfolded protein response (UPR), but commit to apoptotic cell death if the stress situation cannot be resolved (1,2). How cells make this decision between life and death remains poorly understood. To gain further insight into this fundamental question, this project will investigate how one ER stress sensor, IRE1alpha, commits cells to apoptotic cell death.
IRE1alpha is a transmembrane protein of the ER with cytosolic protein kinase and endoribonuclease (RNase) domains (1). Its ER luminal domain senses ER stress and activates its protein kinase and RNase domains to generate the ER stress signal. The RNase domain is thought to produce a largely cytoprotective signal by processing the mRNA for the transcription factor XBP1, while its protein kinase domain has been implicated in activating apoptotic signalling. This project will make use of a unique version of IRE1alpha developed at Durham University that can be activated independent of inducing ER stress.
The successful candidate will characterise whether activation of this version of IRE1alpha commits mammalian cells to apoptosis, characterise the signalling pathways downstream of IRE1alpha that lead to apoptotic cell death, and characterise which enzymatic activities of IRE1alpha, its protein kinase or endoribonuclease domain, are involved in generating the apoptotic signal. To address these aims, the student will use a range of molecular, cellular, and biochemical techniques, such as the construction of IRE1alpha mutants, stable transfection of mammalian cells, PCR techniques to monitor the RNase activity of IRE1alpha, Western blots to monitor phosphorylation and expression of IRE1alpha and apoptotic proteins, and cell biological assays to measure apoptosis.
Applicants should possess at least a 2:1 Honours degree, or equivalent, in an appropriate subject (e.g. biochemistry, cell biology, molecular biology, or genetics).
2. Brown, M., Strudwick, N., Suwara, M., Sutcliffe, L. K., Mihai, A. D., Ali, A. A., Watson, J. N., and Schröder, M. (2016) An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response. J Cell Sci 129, 2317-2328
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