Esposito, Francesco (2008) High Mobility Group A1 (HMGA1) proteins regulate p53-mediated transcription of Bcl-2 gene. [Tesi di dottorato] (Inedito)

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: High Mobility Group A1 (HMGA1) proteins regulate p53-mediated transcription of Bcl-2 gene
Data: 30 Novembre 2008
Numero di pagine: 103
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Biologia e patologia cellullare e molecolare "L. Califano"
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 21
Coordinatore del Corso di dottorato:
Data: 30 Novembre 2008
Numero di pagine: 103
Parole chiave: HMGA1, p53, Bcl-2
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 05 Nov 2009 16:00
Ultima modifica: 30 Apr 2014 19:35
DOI: 10.6092/UNINA/FEDOA/3043


The high mobility group A (HMGA) non-histone chromosomal proteins constitute a subgroup of HMG accessory factors that play key roles in chromatin architecture and orchestrate the assembly of nucleoprotein complexes involved in gene transcription, replication, and chromatin structure through a complex network of protein-DNA and protein-protein interactions. HMGA overexpression and gene rearrangements are frequent events in human cancer, but the molecular basis of HMGA oncogenic activity remains partially unclear. Recently, we have defined a new physical and functional interaction between HMGA1 and p53. This interaction modulates the transcription of p53 target genes such as Mdm2, p21waf1, Bax, and inhibits p53-mediated apoptosis. Moreover, we have described a new mechanism through which HMGA1 inhibits p53-mediated apoptosis by counteracting the p53 proapoptotic activator homeodomain-interacting protein kinase 2 (HIPK2), which binds to and activates p53 by phosphorylating it at Ser46. We found that HMGA1 overexpression promoted HIPK2 relocalization from the nucleus to the cytoplasm, with consequent inhibition of p53 apoptotic function. During my doctorate course, I looked for other target genes that could be regulated by the HMGA1-p53 complex. So, I focused my attention on the apoptosis inhibitor gene Bcl-2, because this gene belongs to Bax family, is regulated by p53, and its promoter has several possible target regions for the HMGA1 proteins binding. I demonstrated that HMGA1 binds Bcl-2 promoter in vitro and in vivo, and that this binding exerts regulatory effects on Bcl-2 transcription. In fact, HMGA1 is able to abolish the repression promoted by p53 on Bcl-2 expression. This effect, as for the Bax promoter regulation, is due to HIPK2 delocalization, from the nucleus to the cytoplasm. Therefore, also Bcl-2 is a gene regulated by HMGA1-p53-HIPK2 complex. Subsequently, my studies were focalized in finding other possible components of this multiprotein complex. Using the neuronal cell line ND7, I found that the transcription factor Brn-3a belongs to this complex. Brn-3a is one of the most important activators of Bcl-2 transcription but, when p53 is overexpressed, it acts as a corepressor for this gene. Moreover, the binding of Brn-3a to its consensus sequences is positively regulated by HIPK2. I demonstrated that HMGA1 overexpression, in this cellular context, promotes not only HIPK2 delocalization from nucleus to the cytoplasm, but also the reduction of Brn-3a binding to the Bcl-2 promoter, removing Brn-3a from its role of corepressor following p53 overexpression. These data support the causal role suggested for the HMGA1 proteins in the neoplastic transformation and provide another mechanism of inactivation of p53 apoptotic function

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