The endoplasmic reticulum (ER) is a major compartment within the eukaryotic cell and is responsible for a variety of functions including synthesis and folding of secretory proteins. A balance exists between protein synthesis and the folding capacity within the ER. If this is disrupted then a series of signalling pathways called the unfolded protein response (UPR) is activated. This response includes transcriptional upregulation, protein translation attenuation and activation of ER associated degradation (ERAD). If however the effort to rectify the imbalance is not successful, then the UPR switches from being pro-cell survival to eliciting an apoptotic response.
The UPR is activated in a variety of human tumours and is one of several mechanisms tumour cells exploit to survive hypoxic conditions. The ERN1-XBP1 branch of signalling is particularly important in Multiple Myeloma. Along side its role in the UPR response, XBP1, is an important factor for plasma cell differentiation, and is dysregulated in myeloma cells. Inhibition of this branch of signalling represents an interesting target for therapeutic intervention in cancer.
My lab will focus on gaining structural and mechanistic insights into components of the unfolded protein response, towards a better understanding of how the UPR signal is activated and its subsequent propagation.
Lab webpage: http://www.imperial.ac.uk/ali-lab