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- Podraza-Farhanieh, Agnieszka, 1991
(författare)
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Exploring mechanisms of insulin secretion regulators using C. elegans
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes mellitus is a group of disorders characterized by disrupted glucose homeostasis. Diabetes is one of the most dangerous diseases worldwide since it affects currently more than 500 million people. The pathogenesis of the disease is associated with the insufficient production of insulin and is characterized by increased blood glucose levels. Insulin secretion takes place in pancreatic β-cells in the response to elevated glucose levels and is regulated by various factors. This thesis is aimed to understand the functions of three proteins and characterize their novel roles in the regulation of insulin signaling and secretion. The first study showed the role of ENPL-1 in the positive regulation of insulin secretion. Loss of enpl-1 resulted in reduced insulin signaling and inhibited insulin secretion. Furthermore, we identified proinsulin as a novel client protein of ENPL-1 and showed that ENPL-1 was required for its maturation. The next study was based on the previous findings showing that ASNA-1 is a positive regulator of insulin secretion. Our study showed that ASNA-1 is present in two redox states, oxidized and reduced and that the multiple functions of ASNA-1 are dependent on its redox states. Our analysis showed, that forcing ASNA-1 into the oxidized state, reduced its function of inserting tail-anchored proteins into the endoplasmic reticulum, without affecting the insulin secretion function. In the next study, we focused on the mutual role of both previously mentioned proteins. We identified the interaction of ASNA-1 and ENPL-1 and showed that proinsulin is required for this interaction to take place. Our study indicated that oxidized ASNA-1 rather than the reduced form was likely interacting with ENPL-1. In the last study, we focused on the role of a third protein, SMN-1, and its impact on the regulation of insulin secretion. Our analysis showed that loss of SMN-1 resulted in neuropeptide secretion defect and caused redistribution of insulin from its original place. In summary, we characterized the functions of three proteins and indicated their importance in the regulation of insulin secretion processes.
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| 2. |
- Raj, Dorota, et al.
(författare)
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Identification of C. elegans ASNA-1 domains and tissue requirements that differentially influence platinum sensitivity and growth control.
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 18:12
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Tidskriftsartikel (refereegranskat)abstract
- ASNA1 plays an essential role in cisplatin chemotherapy response, type 2 diabetes, and heart disease. It is also an important biomarker in the treatment response of many diseases. Biochemically, ASNA1 has two mutually exclusive redox-modulated roles: a tail-anchored protein (TAP) targeting function in the reduced state and a holdase/chaperone function in the oxidized state. Assigning biochemical roles of mammalian ASNA1 to biomedical functions is crucial for successful therapy development. Our previous work showed the relevance of the C. elegans ASNA-1 homolog in modeling cisplatin response and insulin secretion. Here we analyzed two-point mutants in highly conserved residues in C. elegans ASNA-1 and determined their importance in separating the cisplatin response function from its roles in insulin secretion. asna-1(ΔHis164) and asna-1(A63V) point mutants, which both preferentially exist in the oxidized state, displayed cisplatin sensitivity phenotype as well as TAP insertion defect but not an insulin secretion defect. Further, using targeted depletion we analyzed the tissue requirements of asna-1 for C. elegans growth and development. Somatic depletion of ASNA-1 as well as simultaneous depletion of ASNA-1 in neurons and intestines resulted in an L1 arrest. We concluded that, targeting single residues in ASNA-1 affecting Switch I/Switch II domain function, in comparison to complete knockdown counteracted cisplatin resistance without jeopardizing other important biological functions. Taken together, our study shows that effects on health caused by ASNA1 mutations can have different biochemical bases.
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