title: A regulatory mechanism involving TBP-1/Tat-Binding Protein 1 and Akt/PKB in the control of cell proliferation.
abstract: 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. We and others reported that over expression of TBP-1 diminishes cell proliferation in different cellular contexts with mechanisms yet to be defined. Accordingly, we demonstrated that TBP-1 binds to and stabilizes the p14ARF oncosuppressor increasing its anti-oncogenic functions. However, TBP-1 restrains cell proliferation also in the absence of ARF, raising the question of what are the molecular pathways involved. Herein we demonstrate that stable knock-down of TBP-1 in human immortalized fibroblasts increases cell proliferation, migration and resistance to apoptosis induced by serum deprivation. We observe that TBP-1 silencing causes activation of the Akt/PKB kinase and that in turn TBP-1, itself, is a downstream target of Akt/PKB. Moreover, MDM2, a known Akt target, plays a major role in this regulation. Altogether, our data 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.
authors: Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Naples, Italy.
authors: Maria
authors: M
authors: Sepe
authors: Luisa
authors: L
authors: Festa
authors: Fabio
authors: F
authors: Tolino
authors: Luca
authors: L
authors: Bellucci
authors: Luca
authors: L
authors: Sisto
authors: Daniela
authors: D
authors: Alfano
authors: Pia
authors: P
authors: Ragno
authors: Viola
authors: V
authors: Calabrò
authors: Vittorio
authors: V
authors: de Franciscis
authors: Girolama
authors: G
authors: La Mantia
authors: Alessandra
authors: A
authors: Pollice
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D002460:Cell Line; D049109:Cell Proliferation; D002999:Clone Cells; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism
chemical_list: D016895:Culture Media, Serum-Free; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C064757:PSMC3 protein, human