a. Glucose Regulatory Protein (GRP58) is a unique human protein that contains bo

Question

a. Glucose Regulatory Protein (GRP58) is a unique human protein that contains both a Nuclear Localization Sequence (NLS) and an N-terminal hydrophobic Endoplasmic Reticulum (ER) targeting sequence. Where within the cell would you expect to find GRP58? Explain your answer in three sentences or less. Experimental trials have found that co-treating cancer patients with a drug called Bortezomib in addition to conventional chemotherapeutics increases the effectiveness of the chemotherapy drug. Bortezomib has been shown to inhibit the unfolded protein response (UPR) in the endoplasmic reticulum leading to ER stress. Briefly outline one of the two UPR pathways we discussed in class, and hypothesize about how inhibition of this pathway might contribute to making chemotherapies more effective.

Explanation / Answer

a. Grp58 also known as protein disulfide isomerase 3 is mainly located in the endoplasmic reticulum where it interacts with chaperones (calreticulin and calnexin) and helps in the proper folding of newly formed glycoproteins and in the assembly of major histocompatibility class I proteins. However, it is also found in the nucleus as well as in the cytoplasm.

b. Accumulation of improperly folded proteins in the ER lumen results in the activation of UPR response. Upregulation of misfolded proteins in the cell results in the dissociation and activation of Grp78 by homodimerization and oligomerization. This leads to the activation of PERK (protein kinase RNA-like ER kinase). Activated PERK inturn activates eIF2 alpha which results in the arrest of protein translation and subsequent arrest of cell cycle. Also, activation Grp78 , activates IRE1 (inositol-requiring protein 1 alpha), which facilitates the formation of XBP1 (X-box binding protein 1). Activating transcription factor 6alpha signaling is also activated during the process of ER stress. Activation of all these signaling pathways result in an increased folding of proteins and transport and ER-associated protein degradation (ERAD). During this process of UPR, protein synthesis is attenuated. Inhibiting UPR pathway results in the accumulation of misfolded proteins in the cell with the result the cells undergo apoptosis. Therefore, a chemotherapeutic drug that targets this UPR pathway results in cellular apoptosis.

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