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The unfolding protein response - quantitative analysis and post-transcriptional regulation of bip protein expression


Research objectives and content
Perturbance of the endoplasmic reticulum (ER), either by the synthesis of mutant proteins or by the action of certain pharmacological reagents, lead to the accumulation of malfolded proteins in the organelle, which in turn elicits the unfolding protein response (UPR). This pathway has been described mainly as a transcriptional response that increases the levels of ER- resident chaperones such as BiP, therefore restoring ER function. Despite the progress in our understanding of the UPR, an accurate quantitative description of the pathway is lacking, and little attention has been payed to the possible involvement of post-transcriptional pathways that may regulate also the level of ER- chaperones. So, the objectives of our project are: (1) To analyze quantitatively the UPR For this purpose we will use HeLa cells stably transfected with the non-secreted immunology light chain under the control of a tetracyclin-dependent promoter. This could allow us to vary the expression of the light chain by 5 orders of magnitude. (2) To establish the importance of post-transcriptional pathways in the expression of ER-chaperones, specially BiP. We will use the same system as above but also expressing other protein constructs as stated in the RESEARCH PROJECT.
Training content (objective, benefit and expected impact)
The main objective is to obtain a detailed quantitative analysis of the UPR and to stablish the role of post-transcriptional pathways in the expression of ER-chaperones. This will have special relevance in three aspects: basic research, health care and biotechnology. Concerning the first, the UPR is a very important pathway controlling the level of ER-chaperones and therefore the level of secretory and membrane proteins in the cell, and is probably finely regulated. Regarding the second, one can hypothesize that proper levels of ER-chaperones might alleviate some well-known genetic disorders. So, knowing the UPR more accurately may provide new tools for therapy. Finally, about the third point, the production of many secreted polypeptides of industry and medical interest should potentially be improved by regulating the UPR This could only be done if the pathway is well-known at the molecular level.
Links with industry / industrial relevance (22)


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