HIGH-MOBILITY GROUP A1 (HMGA1) PROTEIN INHIBITS P53-MEDIATED INTRINSIC APOPTOSIS INTERACTING WITH Bcl-2 AT MITOCHONDRIA

TORNINCASA, MARA (2011) HIGH-MOBILITY GROUP A1 (HMGA1) PROTEIN INHIBITS P53-MEDIATED INTRINSIC APOPTOSIS INTERACTING WITH Bcl-2 AT MITOCHONDRIA. [Tesi di dottorato] (Inedito)

Full text disponibile come:

[img]PDF - Solo per gli Amministratori dell'archivio fino a 30 Gennaio 2013 - Richiede un editor Pdf del tipo GSview, Xpdf o Adobe Acrobat Reader
1851Kb

Abstract

ABSTRACT The High mobility group A (HMGA) non-histone chromosomal proteins play key roles in chromatin architecture and orchestrate the assembly of nucleoprotein complexes involved in gene transcription, replication, and chromatin structure. HMGA overexpression and gene rearrangement are frequent events in human cancer. Their importance in cancer progression and their role in apoptosis has been defined by a new physical and functional interaction between HMGA1 and p53 proteins. HMGA1 inhibits p53-mediated apoptosis modulating the transcription of p53 target genes as Mdm2, p21Waf1, Bax, Bcl-2 and promoting Hipk2 relocalization from the nucleus to the cytoplasm. Even though HMGA1 proteins have been identified as nuclear proteins, abundant HMGA1 expression has been frequently detected in the cytoplasm of cancer cells but it has been often considered as an artefact likely do a very abundant HMGA1 expression, and no deep investigation has been undertaken to clearly demonstrate the presence of these proteins in the cytoplasm, and to unveil the functional role of this localization. Preliminary studies obtained by a screening of an Antibody ArrayTM strongly suggest possible cytoplasmic interactors of HMGA1 proteins in tumoral cell lines. My thesis project is focalized on the interaction between HMGA1 and anti-apoptotic factor Bcl-2. I have identified and characterized a new subcellular localization of HMGA1 proteins by analysis of total, nuclear and cytoplasmic cell lysates from several normal, and tumor-derived cell lines. Then, I confirmed the interaction HMGA1-Bcl-2 in cytoplasm in vivo and in vitro. Moreover, since p53 interacts with Bcl-2 blocking its anti-apoptotic function, I identified a new mechanism that allows HMGA1 proteins to inhibit the p53-mediated intrinsic-apoptotic pathway. Indeed, HMGA1 localizes at mitochondria and displaces it from the binding to Bcl-2 enhancing its anti-apoptotic function. Finally, I reported the correlation between the HMGA1 cytoplasmic localization and a more aggressive phenotype in thyroid, breast and colon cancer.

Tipologia di documento:Tesi di dottorato
Parole chiave:CANCER, HIGH-MOBILITY GROUP A1 PROTEINS, APOPTOSIS, p53, MITOCHONDRIA
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/05 PATOLOGIA CLINICA
Area 06 Scienze mediche > MED/04 PATOLOGIA GENERALE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
AVVEDIMENTO, ENRICOavvedim@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
FUSCO, ALFREDOalfusco@unina.it
Stato del full text:Inedito
Data:Novembre 2011
Numero di pagine:75
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Biologia e patologia cellullare e molecolare "L. Califano"
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Patologia e fisiopatologia molecolare
Ciclo di dottorato:24
Numero di sistema:8754
Depositato il:13 Dicembre 2011 12:26
Ultima modifica:23 Aprile 2012 11:23

Solo per gli Amministratori dell'archivio: edita il record