Unit:
Τομέας Γενετικής και ΒιοτεχνολογίαςLibrary of the School of Science
Author:
Κόττα-Λοΐζου Ιόλη
Dissertation committee:
Μ. Α. Τύπας Καθηγητής ΕΚΠΑ (επιβλέπων), Π. Μαυρομαρά Καθηγήτρια Δημοκρίτειου Πανεπιστημίου Θράκης, Α. - Μ. Παππά Επίκ. Καθηγήτρια ΕΚΠΑ
Original Title:
Μοριακοί μηχανισμοί έκφρασης και λειτουργικότητας της αμινοτελικής περιοχής της πολυπρωτεΐνης του ιού της ηπατίτιδας C
Translated title:
Molecular mechanisms of expression and function of the amino-terminal domain of the Hepatitis C virus polyprotein
Summary:
Hepatitis C virus (HCV) is a major cause of chronic liver disease and can lead
to hepatocellular carcinoma. The single-stranded positive-sense RNA genome of
HCV encodes at least 10 proteins, including core+1/ARFP. The aim of this PhD
thesis was to study core+1/ARFP expression in the more physiologically relevant
HCV replicon system and investigate core+1/ARFP functions and their mechanisms.
In order to investigate the molecular mechanism controlling core+1/ARFP
synthesis in a more physiologically relevant system, the HCV replicons were
used combined with luciferase-tagging experiments and site-directed mutagenesis
studies. These results suggest the expression of the core+1 open reading frame
from the viral genome and provide strong evidence for the synthesis of two
core+1/ARFP isoforms by different alternative translation mechanisms. In
addition, by the use of reporter assays and HCV replicons, we show that
core+1/ARFP decreases the expression of hepcidin, the main regulator of iron
metabolism, in hepatoma cells. The Activator Protein (AP) 1 binding site of the
human hepcidin promoter, relevant to the basal promoter activity, is also
essential for the downregulation by core+1/ARFP. In conclusion, we provide
evidence that core+1/ARFP downregulates AP1-mediated transcription, providing
new insights into the biological role of core+1/ARFP, as well as the
transcriptional regulation of hepcidin.
Keywords:
Hepatitis C virus, Core+1/ARF protein, Hepcidin, Tranlational mechanisms, Transcriptional regulation
Number of references:
341
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