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Identifier

000388725

Title

The role of Usp22 de-ubiquitinase in the regulation of metabolic and carcinogenesis pathways

Alternative Title

Ο ρόλος της αποβουκιτινιλάτης Usp22 στη ρύθμιση του μεταβολισμού και του καρκίνου

Author

Μπάλιου Στυλιανή

Thesis advisor

Καρδάσης, Δ.

Reviewer

Σαββάκης, Χ.
Ταλιανίδης, Ι

Abstract

USP22 is a thiol-specific protease that can remove ubiquitin from ubiquitinated histones H2A and H2B. USP22 has been recently identified as a member of the 11-gene cancer stem cell signature proposed to serve as a predictor of treatment resistance, tumor aggressiveness and metastatic potential of human cancers. Studies in yeast indicate a critical role for Usp22 in transcriptional initiation and elongation. However, its role in mammals remains elusive. We aimed to address the role of Usp22 in the mouse liver. Our work focuses on the role of Usp22 in metabolic regulation, cell cycle progression and hepatocarcinogenesis. Preliminary results using wild-type mice under conditions of fasting indicated increased levels of Usp22 compared to normally fed controls. Additionally, when mice were subjected to partial hepatectomy increased levels of Usp22 were observed. Consistent with a potential role of Usp22 in cell proliferation, analysis of livers from mice bearing experimentally induced tumors also indicated upregulation of Usp22, compared to normal age-matched livers. In all cases, Usp22 displayed nuclear localization, similar to untreated livers, as assessed by immunohistochemical analysis. Our results indicate a putative involvement of Usp22 in metabolic regulation and in cell cycle progression in murine liver. We are currently in the process of generating three genetic models that will be useful for studies aimed at understanding Usp22 function in liver. The first one is an Usp22 conditional liver-specific knock-out mouse, the second is a transgenic mouse overexpressing human USP22 upon tamoxifen treatment and the third one is a transgenic mouse overexpressing a catalytically inactive C185S mutant form of human USP22. Phenotypic characterization, genome wide expression and occupancy analysis of these models will be useful towards elucidating the role of Usp22 and the dynamics of histone ubiquitination in the mammalian liver.

Language

English

Subject

Cell cycle progression

Hepatocarcinogenesis

Metabolic regulation

Usp22

Εξέλιξη του κυτταρικού κύκλου

Ηπατοκαρκινογένεση

Ρύθμιση του μεταβολισμού

Issue date

2014-12-04