Festa, Luisa (2011) TBP-1 (TAT BINDING PROTEIN-1) IN THE CONTROL OF CELL PROLIFERATION: FUNCTIONAL RELATIONSHIP WITH THE AKT/PKB SIGNALING PATHWAY. [Tesi di dottorato] (Unpublished)

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TBP-1/Tat-Binding Protein 1 (also named Rpt-5, S6a or PSMC3) is a multifunctional protein, originally identified as a regulator of HIV-1-Tat mediated transcription. It is an AAA-ATPase component of the 19S regulative subunit of the proteasome and, as other members of this protein family, fulfils different cellular functions including proteolysis and transcriptional regulation. Consistent with the role in protein destruction, TBP-1 has been shown to enhance the ubiquitin ligase function of the VHL (Von-Hippel-Landau) tumour suppressor toward Hif1α and to be involved in the degradation of Fra-1 (Fos related antigen -1), both overexpressed in a variety of human cancers. Moreover, TBP-1 binds to and stabilizes the p14ARF human oncosuppressor, likely avoiding its entrance into the proteasome and increasing its anti-oncogenic functions. Intriguingly, TBP-1 overexpression can inhibit cell proliferation in a different celllular contexts suggesting that it may function as a negative regulator of cell proliferation. Infact, inhibition of the oncogenic phenotype of erb-B transformed cells was accompanied by an increase of TBP-1 intracellular levels and, accordingly, its overexpression in erb-B transformed cells strongly inhibited tumour formation in athymic mice. The results presented here demonstrate that stable reduction of TBP-1 intracellular levels increases cell proliferation, renders cells able to grow also in absence of serum, and increases resistance to serum-deprivation induced apoptosis of primary human fibroblasts immortalized by h-TERT expression. Moreover, TBP-1 silencing determines the activation of the Akt/PKB serin-threonin kinase, one of the major transducers of growth signals mediating proliferative and pro-survival effects. TBP-1 itself turned out to be a downstream target of Akt/PKB and MDM2, a known Akt target, plays a major role in this regulation. Altogether, these results suggest the existence of a negative feedback loop involving Akt/PKB that might act as a sensor to modulate TBP-1 levels in proliferating cells.

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