Μελέτη του ρόλου των αναδιοργανωτών της χρωματίνης στην αποπτωτική απόκριση των κυττάρων (Doctoral thesis)
Multiple cellular processes, including gene silencing, cell growth, DNA repair and apoptosis are regulated by the dynamic structure of chromatin. In this study we investigated the role of two histone chaperones, prothymosin α and SET/TAF-I β, which have been implicated in diverse processes, such as chromatin remodeling and cell death, in the regulation of the mitochondrial apoptotic pathway. Our data showed that the expression pattern of prothymosin α is altered during apoptosis induced upon treatment of cancer cells with chemotherapeutic drugs and an apoptotic form of ProTα is generated by proteolytic cleavage by caspase-3. Confocal microscopy experiments showed that the apoptotic ProTα is translocated from the nucleus to the cytoplasm and the cell periphery upon induction of apoptosis. Overexpression of prothymosin α in HeLa cells confers resistance towards apoptosis induced upon cisplatin and etoposide treatment. In accordance to these findings, silencing of prothymosin α sensitizes cells to apoptosis. Our data support the notion that prothymosin α exerts an anti-apoptotic role in cancer cells treated with chemotherapeutic drugs. On the contrary, changes of SET/ΤAF-1β expression levels do not affect the apoptotic response of the cells. Chromatin remodeling complexes have essential roles in many aspects of T-cell development. Furthermore, the generation of a functional T cell’s repertoire is tightly regulated by the apoptotic machinery at different stages and levels. To investigate the role of prothymosin α, through its anti-apoptotic function, in T-cell development, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). These HSCs were infected with retroviruses expressing wild type prothymosin α, the constitutively active apoptotic mutant of prothymosin α and a dominant negative prothymosin α mutant, which bears a disrupted caspase-3 recognition site. The differentiation process of the infected T cell precursors through DN, DP and SP developmental stages was followed by multiparameter flow cytometry. Our data showed that T cell maturation was not affected by alterations on the expression levels of the wild type or the mutant forms of prothymosin α. However, our work designates prothymosin α as a putative target molecule for the elaboration of strategies to modulate apoptosis, linked to this protein (inactivation, mutation), that may lead to the conception of new chemotherapeutic approaches
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων Σχολή Ιατρικής Τμήμα Ιατρικής Τομέας Λειτουργικός - Κλινικοεργαστηριακός Εργαστήριο Βιολογικής Χημείας|
|Appears in Collections:||Διδακτορικές Διατριβές|
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