Investigations into the effect the Bcl-2 family proteins have on activation of the unfolded protein response pathway.

Triona Conneely

The endoplasmic reticululm (ER) is concerned with the folding, modification and formation of newly synthesized proteins. Disturbances to the environment of the ER can lead to lethal effects due to the aggregation of unfolded proteins. Eukaryotic cells however, have evolved an adaptive protective pathway termed the unfolded protein response (UPR) to maintain the function of the ER. The UPR is a three pronged attack to alleviate the stress of unfolding proteins in the ER. The first approach is inhibition of general protein synthesis, the second is induction of ER chaperones that assist protein folding and the third is increased protein degradation. Three transmembrane transmitter molecules are involved in the UPR pathway PERK, ATF-6 and IRE-1. The aim of this study was to examine the effect of the Bcl-2 family on activation of these transmitter molecules. The question was approached from two avenues; firstly an overexpression study was carried out to investigate the role of overexpression of Bcl-2 on activation of the UPR. Following this Bcl-2 was targeted to different organelles and its functions were evaluated from the various locations. The second part of the project examined the effect of knockdown of Bax and Bak on initiation of the UPR pathway.

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